Karen was raised by an alcoholic mother. During high school, she was involved with Jason Quartermaine, but she was meant to be with Jagger Cates. Brenda Barrett also wanted Jagger, and she schemed to keep Jagger and Karen apart. Eventually, Jagger and Karen got together only to have Karen remember that she was molested by her mothers boyfriend, Ray Conway. She began going to seedy places, where she met Stone, Jagger's long lost brother, but she did not know this at the time. Stone introduced her to Sonny, and she began stripping in his club, the Paradise Lounge. She also got hooked on pills at this time, since she was participating in a summer program at GH for future doctors, and she was stripping at night. During this time she had a brief affair with Sonny. Alan Quartermaine caught her stealing drugs, and she confessed the abuse to Gail Baldwin, who was not known to be her grandmother at the time. She and Jagger got back together, and they got married when he got accepted into the police academy in Chicago. Alan offered to pay Karen's expenses through medical school. They came back for brief visit when Stone was dying. Sometime after that they moved to San Francisco where Jagger became an undercover cop. This year, Karen returned to Port Charles as an intern at GH, leaving Jagger behind in San Francisco. The physical distance between them soon led to a much more painful distance. Karen and Jagger's marriage crumbled and they were divorced in the winter of 1997.

Karen was then engaged to Joe Scanlon, but they called the engagement off when Frank and Courtney made Joe look like a sex addict. However, Karen found out it was Frank framing Joe but didn't find out Courtney was helping him. Joe and Karen are friends again, but not engaged (yet.) Joe is still trying to recover from the framing and hasn't yet proposed to Karen again since Karen didn't trust him when he was being framed.

Karen and Joe tried again, but ultimately ended their relationship to part as friends. Karen became chief resident, facing some resentment from fellow doctors as she had to take a more active role in their cases and decisions. During the nurse's strike, the pressure got to her and she took pills from the GH pharmacy. Eventually, she admitted her addiction to Alan and went to rehab.

Despite his past crimes against her, Karen was drawn to the kinder, gentler Frank, and they began dating. Around this time, Frank found an old computer at a garage sale which mysteriously connected him Cookie, to a troubled young girl in 1973. Meanwhile, Rhonda had fallen off the wagon due to painful past memories. Karen learned of her aunt Caroline (Karen's namesake and doppelganger), who had died at age 18 after being hit by a car. Frank's efforts to help Cookie ended in his successfully persuading not to attend a dance and "go all the way" with a boy who liked her. As soon as he convinced her, Karen vanished into this thin air. Frank realized he'd been communicating with the teenage version of Rhonda, and had stopped her from conceiving Karen. By traveling to the past, he corrected history, returning Karen to the time stream. Karen learned of what had happened, and she and Frank kept the developments as their own little secret.

Karen and Frank were then baffled by the behavior of Gabriella, Joe's girlfriend. Her dumping him led to him leaving town. Soon after, Frank's EMT partner Emilio (Gaby's brother) was attacked and drained of blood, not the only patient to have this problem. When Karen and Frank learned of the vampirism plaguing Port Charles, they joined in the efforts to destroy Caleb, nearly dying when a room they were all in caught fire.

Chris was secretly doing experiments on a sample of Gaby's blood. Karen discovered him about to inject himself with the syringe, and in their struggle, she was jabbed with the needle instead. She began developing superpowers, not to mention an increased libido. The horrible side effect was that she would quickly age and die. Frank secretly made a deal with Frank that he would leave town if Chris (who wanted Karen) gave Karen the antidote. Lucy's angel cousin Rafe stepped in and managed to have Karen cured while reuniting Frank and Karen.

Karen and Frank had a few happy months, but spring 2002 would begin a great time of upheaval and self-doubt for Karen. First, her best friend Eve died, and Karen was too devastated to even finish her eulogy. Next, Frank began behaving abusively on the very night he proposed marriage. He saw her in a red slip and repeatedly called her "whore" and claimed that he "knew what she wanted". He brought up her past as a stripper and said she was worthless. Karen became close to Ricky Garza, who saved her from Frank's rages a few times. Frank became so out of control that Karen had to institutionalize him for his own safety after he went at Ricky with a knife. Karen kissed Ricky one day at his apartment, but he told her about a magical candle marked DESIRE, how the candle had been responsible for Frank's condition. Karen slapped him and accused him of manipulating Frank into going crazy.

Karen gave Frank another chance, but one day at the Recovery Room, Frank had an episode with no candles around. Karen was being interviewed for the local news, and Frank thought she was coming onto the reporter. He ripped open her blouse and verbally abused her, humiliating her in front of potentially millions of viewers. Karen was laughed at during work, received endless crank calls, and was even asked to pose nude in a men's magazine. She began to ponder if she liked being bad, if she had enjoyed her days as a stripper. Returning to the Paradise Lounge, she was considering returning as a dancer when Ricky met up with her. He made her dance for him, and as she went through her routine, she realized exactly what he wanted her to - that she felt sick and dirty, not excited.

Ricky was the only person Karen could now count on, and she had sex with him. She told him it couldn't happen again, because of their differences in age and background and personality, but fell into bed with him again soon after. Meanwhile, Frank had discovered the source of his mental illness, and asked Karen to let him prove that he was now sane. Frank lit the DESIRE candle in front of her and didn't go crazy. Strangely enough, Karen was affected, seeing herself with Ricky. Yet, in spite of her strong feelings for Ricky, she had a long history with Frank and decided to try again. Karen told him she had been intimate with Ricky, and he understood. What Karen didn't realize was that he was still unstable, and was now picturing her in lurid situations with Ricky.