Lincoln spills one of Lisa's experiments, setting off a chain reaction throughout the house.
Lincoln is practicing his yo-yo tricks, when his yo-yo flies off of his finger, and into Lisa's bedroom, breaking the beakers on her desk, and spilling their contents. Fearing how angry Lisa might be when she finds out what he did, Lincoln decides not to tell her who did it, asking "What's the worst that can happen?", and removes the evidence from the scene. Afterward, a stray drop from one of Lisa's formulas causes an explosion that blows a hole that exposes Lori and Leni's closet.
While overseeing the damage, Lori finds a signed photo of Bobby on Leni's side of the closet, which Leni claims was her "88-day-iversary" gift that she forgot to give to her. Lori assumes the two have been dating each other behind her back, and angrily disowns Leni. She storms out of the room and slams the door behind her, causing the coat rack in the closet to fall on Leni's head, knocking her unconscious. When she awakens, Lincoln and Lisa discover that the concussion had made Leni even smarter than Lisa, as evidenced when she corrects Lisa on a complex equation she believed she had solved correctly. Feeling that her world has been shattered, Lisa gives up on science and gets a job as a gas station attendant at Flip's Food & Fuel.
Later, Lynn comes home, enraged that she just got kicked off every one of her sports teams due to her failing school (since Lisa no longer tutors her), and angrily kicks her soccer ball, which hits Lola in the face. Lola gets a hideously swollen nose from the hit, which makes her think she looks like a "monster". When Lincoln tries to encourage Lola not to say that, she runs back upstairs in despair but accidentally trips on the last step, causing her to fall face first on the floor, and lose all but one of her teeth, much to her despair. Lincoln tries to convince Lisa to come back, but she refuses, especially when Leni shows up, arrogantly boasting that she won the Nobel Prize for inventing a car fueled by apple juice, and got accepted into Harvard, which she then drives off to.
Back home, Lola has decided to run away to avoid being reminded of her former beauty while Lana, not wanting to suffer like her, decides to walk around in a plastic bubble for her own protection. Meanwhile, Luna records a music video she wrote about her family falling apart. It becomes so successful that Mick Swagger recruits her to join his tour. Lincoln tries to call Clyde to help him fix the insanity he caused, but he can't because now, since Lori broke up with Bobby, she's dating him for the rebound and they are skydiving together, much to Lincoln's disgust. Luan enters Lincoln's room to announce that she's giving up comedy to become an activist, due to watching too much cable news following Luna's departure (since she no longer has anyone to try her jokes out on). She has also liberated all of Lana's pets, who all run wild throughout the house.
While trying to subdue the rampaging animals, Lincoln watches several reports on the news detailing the fates of his sisters; Luna has been kicked off the Mick Swagger tour after destroying her hotel room in a fit of rage, Luan has chained herself to a giant redwood tree, and Lynn and Lola are on the lam after robbing the gas station Lisa works at. Lucy appears, announcing to Lincoln that she is now a vampire from being bitten by Lana's liberated bat, and she turns into one herself. At his wit's end, Lincoln figures that he still has to save his remaining sister, Lily, only to find that she's not in her crib. Instead, Lisa's spilled chemicals have caused her to grow into a giant bigger than the house, where she lifts up the roof so she can grab Lincoln and devour him.
Suddenly, everything cuts back to before Lincoln removed the evidence, revealing all the chaos was only Lincoln imagining a worst-case scenario for not telling Lisa. Lisa enters the room, causing Lincoln to confess that he ruined her experiment. However, instead of being angry, Lisa's happy and hugs Lincoln--when Lincoln expresses confusion as to why Lisa isn't mad, she explains that she was actually hoping for something like this to happen as part of an experiment she was doing. Lisa's also happy that Lincoln did the right thing by confessing to what he did instead of lying to her or just not telling her about it. Lincoln's relieved that things are normal in the house, only to see, to his horror, Lori and Clyde riding by on a tandem bike, apparently having gotten married.
Leni drives a car suggesting that she passed her driving test albeit in the fantasy.
Charles appears to be very intelligent due to the fact that he can use a phone and that Lincoln can understand what he said. However, considering it occurred in Lincoln's fantasy, it's unknown how much of this intelligence the real Charles possesses.
At the end of the episode, Clyde and Lori are riding the tandem bicycle from "Hand-Me-Downer."
Although all of Lincoln's sisters appear in this episode, Lisa is the only sister who "actually" appears (and possibly Lori at the end of the episode, if she isn't another one of Lincoln's hallucinations).
Charles breaks the fourth wall in this episode, when he glances at the viewers after Lincoln decides not to tell Lisa about the incident.
The order in which something negative happens to Lincoln's sisters within his fantasy:
Lori - Disowns Leni and dumps Bobby after believing them to have been seeing each other behind her back, and falls in love with Clyde on the rebound.
Leni - Becomes smarter than Lisa after being hit in the head with a coat rack, becoming extremely arrogant and uncaring in the process, and abandons her family to go to Harvard after winning a Nobel Prize.
Lisa - Gives up her studies and gets a job at Flip's Food & Fuel.
Lynn - Gets kicked off her sports teams for failing her academics, leading her to run away with Lola into a life of crime.
Lola - Gets hit in the face with Lynn's soccer ball and runs away with Lynn into a life of crime after repeatedly injuring herself to the point where she believes she's a hideous monster.
Lana - Protects herself inside a plastic bubble to avoid any injuries.
Luna - Joins Mick Swagger on a world tour, only to get kicked off for trashing her hotel room in a fit of rage.
Luan - Gives up comedy and becomes an activist after watching too much cable news.
Lucy - Turns into a vampire after being bitten by Lana's liberated bat.
Lily - Becomes a giant after being exposed to Lisa's chemicals.
When Luna was interrupted by her video getting more views, she was about to say "hell."
Lincoln rhetorically asks Charles to go poop on the couch, the scene then cuts to Lincoln wiping the couch while scolding the latter who whimpers in shame.
AC/DC - Luna making a song about their family going on a highway to "hello" references their 1979 song "Highway to Hell".
Harvard University - Leni told Lincoln and Lisa that she was heading to this university after winning a Nobel Prize.
Three wise monkeys - When Lincoln shouts, "Where did it all go wrong?!", he, Izzy, and the monkey take on poses by the three "wise monkeys"; Izzy imitates Kikazaru (hear no evil), Lincoln imitates Mizaru (see no evil), and the monkey imitates Iwazaru (speak no evil).
Keep Calm and Carry On - On the side of Lisa's table is a parody poster of this motivational quote from WWII reading, "Keep Calm And Do More Calculus."
Thelma & Louise - Lynn and Lola going on a high-speed chase in the desert is similar to the desert chase scene in this 1991 film.
Good luck trolls - When viewed at a certain angle, Lola's swollen nose resembles the noses of these dolls originally created by Thomas Dam.
DirecTV and UK listings mistakenly titled this episode "The Butterfly Effect."
While Lori is reading what's on the picture of Bobby, she reads "To my bodacious babe" even though it really reads "For my bodacious babe."
After Leni gets hit in the head with a coat rack, she awakens and is shown with bandages wrapped around her head. But as she is leaving Lisa's room right before Lisa gave up her studies, the bandages are gone.
When Lincoln was about to run away from giant Lily, the yo-yo was on Lisa's desk, even though Lincoln took it away.
When Lana says "Careful, Lincoln! You could get seriously injured!", the closed-captions switch the placement of "could" and "get," making it instead read "Careful, Lincoln! You get could seriously injured!"