The episode opens with tension at Meredith's home.  Izzie Stevens knocks on Meredith's bedroom door revealing a naked Derek Shepard haphazardly covered by a towel.  Evidently she needs to pay the pizza guy, but Alex Karev owes money and won't talk to her.  Obviously upset, Derek asks Izzie to step around the corner and yells, "Alex!"  When alex answers, he asks for the twenty and hands it to Izzie.  Problem averted, but Derek is not happy.

The drama between the two continues at the hospital.  Izzie and Alex are assigned the "pit" today and neither is very happy about it. Izzie's first patient needs stitches in his head after being struck in the head with a remote by his wife.  She is so mad at his lack of enthusiasm and tendency to fall asleep all of the time.  She is angry about it and says they're going to be divorced - she can't stand being married to such a boring man.  The wife storms out and Izzie soon notices an unusual response on the corner of the man's mouth.  She orders a CT scan for further evaluation, but an eaves dropping Alex hears about it.  Alex swoops in on the patient and offers to take him personally up for the scan.  The unknowing patient goes with him for the consult.

The patients scan shows that he, in fact, has a large tumor behind his forehead.  Izzie walks in as Derek Shepard and Mark Sloan consult about the patient's procedure.  They will need to pull back the skin over his face in order to access the tumor.  They mention that Alex will be scrubbing in.  Izzie is furious stating that this was her patient.  Derek is not about to get in the middle of it, says Karev brought the case to him, so he's scrubbing in and leaves.  Izzie's attempts to plead with Mark Sloan fall on deaf ears as he explains that "Karev's a cowboy!" and she obviously isn't.  

When George O'Malley comes looking for the residents who are hiding out in the Dermatology department, he tells Izzie to buck up and be the strong woman in all the old westerns that convinces the cowboys what they need to do.  She cynically says they were all "whores."  George explains that even so, they had assets that they used to thier advantage.  The made the cowboys listen.  

While Izzie is busy being angry at Alex, chasing him down, throwing things at him to try to get his attention, the patient's wife is feeling incredibly guilty about her husband's condition.  How could she have been so hard on him and not once considered it was a sign that there was something wrong?  She can't even face him.  Izzie goes to talk to the patient, who is also upset about the whole thing.  What does he have to lose at this point when his wife won't even talk to him?  Izzie tells him to have hope and asks if he is pleased with his "new" doctor.  He says Karev is "okay."  Izzie just happens to drop a couple of personal facts about Alex Karev and how he's coping after some difficulty with a girlfriend and some depression and nonchalantly tries to leave.  The patient suddenly perks up and says he doesn't want a doctor who is off his game to perform his surgery and asks if he can get her back.  She tells him if he wants to, he can request her to Dr. Shepard. 

When Alex hears, he's furious, but Izzie is back on the case. Izzie tells him, "Using me as a doormat is one thing. Screwing with my career is another! I have been wiping your snot and covering your ass for weeks now. And all you've done is abuse me. And for a little while you get to do that because you're heartbroken and pathetic, and I'm a good friend. But it ends now. Get your own surgery and wipe your own snot." Feeling justified as it was her patient in the first place, she is willing to let him just be mad at her.  She looks up at him in the observation deck as she performs the surgery.  Mark Sloan tells her, "Cowboys don't have friends," as he noticed her looking up at him. The surgery is successful.  Izzie goes to tell the wife how the surgery went, but the wife is unsure of whether she can face her husband after all she said to him.  Izzie explains that it's okay, she "just made a mistake."  Alex overhears the conversation. 

Later at Joe's, Alex is sitting alone at the bar.  Izzie approaches and is still mad calling him a "tool!"  He still won't talk to her even though he knows she's right. Just then  Derek Shepard offers to buy the two a drink.  They tell him he's the best roommate ever, but he's not happy, "Just to be clear, if you two ever pull any of that crap with one of my cases again, I will have you thrown out of the program.."  After he leaves, Alex finally admits how angry he has been.  "I know I'm being an ass. I can't help it. I'm pissed off, all the time. So much so that I'm losing my mind. But you can't be pissed at a crazy chick for losing her mind, so there's nobody else for me to be pissed at. Except you. . . I'm pissed off so much that I can hardly breathe sometimes," he tells her.  Izzie just listens, she understands.