Karen met Stan Walker in 1985, brushing off three simultaneous relationships (with Martina Navratilova, Sultan Habibi Shoshani Padush Al-Kabir, and a gentleman named Clayton) to be with him only to learn that he was married. After going through two other marriages, she finally got together with Stan 10 years later. At some point before this, she also agreed to appear non-naked (her costume was a rubber dress) as the star of the fetishistic porn film Next to Godliness, a dominatrix flick.

Her relationship with her maid Rosario Salazar, whom she met and hired in 1985 and for whom she even arranged a marriage with Jack to help her get a Green Card, is very close. Although the duo often bicker and fight, it is only part of the bond they share. In the beginning of the series, it seemed that Rosario didn't speak much English, and Karen had a hard time communicating with her. Karen's way of giving Rosario orders was to add the letter "o" to the end of every word she'd say (e.g., "Enougho with the April Fresho. *hangs up the phone* Right now she's calling me a bitcho"). In another example of miscommunication, Karen used to end phone calls with Rosario by saying "hola," which means "hello" in Spanish and not "goodbye." When Rosario was first seen on-camera at the end of the first season, it was revealed that she spoke English quite well and that Karen was being patronizing. In a later season we see Karen forced to live in an apartment block she owns in Spanish Harlem for failing to bring the building to code. She is seen in this episode screeching at a child in the street in fluent Spanish leading Will to comment "And yet when you talk to Rosario it's 'Scrubbo the Tubbo".

Karen's arch rivals include, but are not limited to, Beverley Leslie (played by Leslie Jordan), Lorraine Finster (played by Minnie Driver), Candice Bergen who is also Karen's best friend referring to her once in a restaurant as "horrible slash delightful. Karen may have also spent time with her in a sky cap. (the actress, whom Karen refers to as "Candy"), Marlo Thomas (Karen hates her, but enjoys her husband, Phil Donohue. Marlo and Phil apparently live in Karen's apartment building but never actually appear in the series). We once see Karen greeting an off-set Marlo at a party by shouting "Marlo Thomas - look at you! Vintage 60's with a plunging neckline - oh and I love your dress too honey!". Further enemies include Scott Woolley (until he fell in love with her; played by Jeff Goldblum), and Candace Pruitt (whom Karen refers to as "Candy" Pruitt; played by Christine Ebersole), who once expressed her thoughts that Karen's voice sounded "like someone strangling an old macaw."

Karen also Has a Nephew (And or Niess) Named Dawn Walker.Dawn was abanded By His Parents at age 10, She then lived with his Aunt Tiffany, After a few years Tiffany Died and Dawn Was on her own. Karen Adopted Dawn Durring Her First Year Being Married To Stanly.Dawn Lived With Karen Untill Age seventeen When he got tired of Karen Feeding her Mint Malonws everyday. When Dawn Tryed to leav, Karen Wen't crazy and And told Dawn No one would Ever Love him as much as she did. When Karen's Husband Stan Died, Dawn Tryed to make peace with Karen But Jacked made Her sit in the back due to his Husbands Lazy Eye. Dawn And Karen Havent seen each other cents.

Sometimes Karen unintentionally reveals to her friends a softer side that is carefully hidden. In one such incident, Karen's husband has a heart attack and may die. Karen discovers that her friends have placed a bet to see who can get her to cry first, so she elaborately punishes each of them by leading them on to think she might break down in their presence. In the end, she has an actual breakdown over the incident, which Grace stumbles in on and consoles her during. Another episode sees Karen and Jack in her mansions with her refusing to let him enter 'the forbidden room'. When Jack finally gains access he discovers it is a nursery which Karen had prepared during a pregnancy scare in an earlier season. Although she agrees to change the room into a liquor storage room, she quickly changes her mind and the audience see her facade crumble in a heartbreaking display of emotion.