Unmarked plot spoilers ahead. Consider yourself warned.
Uglies introduces Tally Youngblood, a teenager (or, more specifically, an 'Ugly') eager for her first operation. Her friend Shay is a different story, though; she wants to stay the way she is. Shay knows of a hideout, called the Smoke, where Uglies can escape to avoid being turned Pretty. When Tally refuses to go with her, Shay escapes on her own, leaving Tally with clues that lead to the Smoke. Tally is then blackmailed by the city's superpowered secret police, the 'Specials': She is told she can't become Pretty until she tells them where the Smoke is. So, following the clues, she goes to the Smoke, intending to infiltrate for the Specials. While there, Tally lives among the other Uglies; eventually, she falls for the Smoke's leader, David. His parents tell her the truth about Pretties (that they put lesions in their brains to make them stupid and compliant). When the government's Special Circumstances troops find the Smoke (they'd enabled Tally with a tracker, that would beep if she tried to destroy it), Tally decides to be used as a test subject for a cure for the lesions. To do that, she needs to be turned Pretty.
In Pretties, Tally lives as a Pretty with her friends, having forgotten most of her adventure. She and her friend Zane are led by clues from an old friend from the now-ruined Smoke. The clues bring her to the truth about the Pretty operation and pills that are supposed to make them aware. She and Zane try to convince the other Pretties to stay 'bubbly' or adrenaline-filled, which helps to negate the effects of the Pretties brain damage. Later, Zane is suffering from further brain damage caused by the pills (there were two, intended for one person to take, with one eating the lesions and the other keeping it from eating the rest of the brain; Zane took the first and Tally the second). He and Tally escape on a hot-air balloon, but Zane is lost along the way. Tally makes her way to the Rusty Ruins, a destroyed city, where David is waiting for her, intending to bring her to the New Smoke. Tally makes him leave, deciding instead to stay with her new love, Zane; this leaves them sitting ducks for the Specials, and before long they are captured. Tally finds Shay back in the city, and Shay gets revenge on Tally by turning her Special.
In Specials, Tally, Shay, and their friends have been operated on again and are now Specials; they've been brainwashed into hunting the people of the Smoke. Zane is now in New Pretty Town and is living with an impairment of motor function due to the brain damage from the pills. Tally and Shay convince him to escape to the Smoke, with the intention of using him to take down the New Smoke. Tally tracks Zane for a while, intending to return him to the city so he can become Special. Zane, who knew she was following, traps her into talking with him. They kiss, but, unhappy with his handicap, Tally runs off. She continues following Zane; a helicopter is ready to take him to the New Smoke. Tally manages to catch a ride on the 'copter without being noticed; the New Smoke, as it turns out, is a city called Diego. There she runs into one of her old ugly friends, who tries to inject her with David's mother's cure. Tally escapes by jumping off a cliff, injuring herself. Unconscious, she's then brought to Diego's hospital. The doctors of Diego attempt to reverse the Special operations, as her body qualifies as an illegal weapon. Shay rescues Tally, who later learns that Diego is at war with her city, and Diego is losing. In the meantime, Tally heads over to the hospital to speak with Zane. She's told that he was further injured during her city's attack, and will never regain consciousness. Zane is taking up much-needed space in the hospital, so Tally bids him goodbye, and he's taken off life-support. Back at her city, Tally tricks the head Special, Dr. Cable, into taking the cure, which prompts her to save an imprisoned Tally from the city council. Tally meets David at the Rusty Ruins and sends a message to David's mother, Shay, and her old friend Peris, telling them that she and David will stay together in the wilderness while the cure spreads around the world, warning that she and David will fight to protect the wild if the cities expand too far and things get ugly.
Tally ends up freeing the Dystopia to a degree and starting an uproar, the 'mind-rain'. This is followed up in Extras, in which people have become less easy to control, necessitating the implementation of an economy for the first time in centuries. This is based on popularity. As one can imagine, Tally is the most popular person in the world. Society is changing, and will continue to do so for quite a while.