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Portland, Oregon paramedic Wyatt Cole is going through a lot at the moment. He struggles to deal with his gambling addiction, demanding surgeon father and his ex-girlfriend, who happens to be a ER doctor. During Wyatt's numerous emergency runs, he ends up treating a drug user and victims of a drunken-driving accident.

Cole still has romantic feelings for ex-girlfriend Alice and tries to help out an old schoolmate who is suffering from leukemia. On the job, Cole treats a priest who is suffering from seizures, but his parish believes that he is possessed. Meanwhile, Alice is thinking of going to the next level with her latest boyfriend.

It's a full moon which means that Cole and Sack have to endure some bizarre emergencies including a man who falls from the sky and then lands on a car, a couple of government agents who are all they seem to be, and an imposter EMT who the two find when they show up for a call from a gay bar. In the meantime, Cole continues to deal with his father's demands.

During heavy fog, Cole and Sack are sent to help out victims of of highway pileup. The two must also help a liver transplant patient get to the hospital and a crane operator who has chest pains. Meanwhile, Cole decides to ask his psychologist mother to help out Sack's son.

Cole has to deal with his father's 60th birthday approaching as well as his relationship with Alice and his mounting gambling problem. He also has to go on an emergency run to assist an underwear model. Meanwhile, Sack decides to enroll his son in a gifted school.

Cole finds himself with a new supervisor: his former nemesis, Kroll, from a competing ambulance company. Sack's son is accepted into the private school, and Alice has child problems of her own, in the form of her boyfriend's problem daughter.

When Lexie's cancer advances, Wyatt attempts to persuade his father to use his influence with the transplant board get her a needed liver. Meanwhile, Krull makes life difficult when he installs surveillance equipment to monitor the paramedics, and Sack feels the burden of his son's school tuition.

Alice's manic-depressive mother, Amanda, makes a whirlwind visit to the ER and leaves Alice struggling to manage her emotions. When Amanda provides Wyatt with some unexpected insight into why Alice broke off their relationship, the truth is almost more than he can take.

When the team responds to a bomb at a clinic, Wyat must make the difficult choice whether to leave a patient as a second bomb threatens. Angela and Harper are followed by Japanese firemen hoping to learn paramedic techniques.

Even though Cole and Sack save a baby during an emergency C-Section, the two are sued by the father because his wife died. The media becomes fanatic over the story, but Cole finds he has one supporter, his own father.

Cole's ambulance ends up getting carjacked by drug fiends. Angela ends up being given the job as temporary dispatcher, but her fellow paramedics are not so happy with her newfound authority.

As the trial nears, a confession puts Sack and Wyatt's partnership in jeopardy.

After LifeShield goes up for sale, Cole and his collegues face a huge crossroads in their lives. Cole also faces a big decision when it comes to Alice, who is contemplating moving to the East Coast for a new job. Meanwhile, Sack receives some disturbing news from the mother of his child, and Angela has a new possibility in her life.