Kaczmarek was born in Milwaukee, Wisconsin, the daughter of Evelyn (née Gregorska), a teacher, and Edward Kaczmarek, a US Department of Defense worker. Of Polish ancestry,[citation needed] she grew up in Greendale, where she was raised a Roman Catholic.
In 1999, Kaczmarek was cast to play Lois in the sitcom Malcolm in the Middle, which premiered on January 9, 2000. TV Guide dubbed her role in the series as a "true breakout; a female Homer Simpson", and critics hailed her for her comic talents. Later, Kaczmarek would credit the show for bringing out her comedic side, saying, "[Before Malcolm] I couldn't even get auditions for comedies. I played very unfunny people."
On July 22, 2011, it was confirmed that Kaczmarek would make a vocal appearance as Red Jessica in the television series Jake and the Never Land Pirates during its second season early 2012.

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