Groening was born on February 15, 1954 in Portland, Oregon, the middle of five children (older brother Mark and sister Patty were born in 1950 and 1952, while the younger sisters Lisa and Maggie in 1956 and 1958, respectively). His Norwegian American mother, Margaret Ruth (nee Wiggum; March 23, 1919 - April 22, 2013), was once a teacher, and his German Canadian father, Homer Philip Groening (December 30, 1919 - March 15, 1996), was a filmmaker, advertiser, writer and cartoonist. Homer, born in Main Centre, Saskatchewan, Canada, grew up in a Mennonite, Plautdietsch-speaking family.

Groening described life in Los Angeles to his friends in the form of the self-published comic book Life in Hell, which was loosely inspired by the chapter "How to Go to Hell" in Walter Kaufmann's book Critique of Religion and Philosophy. Groening distributed the comic book in the book corner of Licorice Pizza, a record store in which he worked. He made his first professional cartoon sale to the avant-garde Wet magazine in 1978. The strip, titled "Forbidden Words," appeared in the September/October issue of that year.  Groening had gained employment at the Los Angeles Reader, a newly formed alternative newspaper, delivering papers, typesetting, editing and answering phones. He showed his cartoons to the editor, James Vowell, who was impressed and eventually gave him a spot in the paper. Life in Hell made its official debut as a comic strip in the Reader on April 25, 1980. Vowell also gave Groening his own weekly music column, "Sound Mix," in 1982. However, the column would rarely actually be about music, as he would often write about his "various enthusiasms, obsessions, pet peeves and problems" instead. In an effort to add more music to the column, he "just made stuff up," concocting and reviewing fictional bands and nonexistent records. In the following week's column, he would confess to fabricating everything in the previous column and swear that everything in the new column was true. Eventually, he was finally asked to give up the "music" column. Among the fans of the column was Harry Shearer, who would later become a voice on The Simpsons.  Life in Hell became popular almost immediately. In November 1984, Deborah Caplan, Groening's then-girlfriend and co-worker at the Reader, offered to publish "Love is Hell", a series of relationship-themed Life in Hell strips, in book form. Released a month later, the book was an underground success, selling 22,000 copies in its first two printings. Work is Hell soon followed, also published by Caplan. Soon afterward, Caplan and Groening left and put together the Life in Hell Co., which handled merchandising for Life in Hell. Groening also started Acme Features Syndicate, which syndicated Life in Hell, Lynda Barry and John Callahan, but now only syndicates Life in Hell. At the end of its run, Life in Hell was carried in 250 weekly newspapers and has been anthologized in a series of books, including School is Hell, Childhood is Hell, The Big Book of Hell, and The Huge Book of Hell. Although Groening has stated, "I'll never give up the comic strip. It's my foundation," he announced that the June 16, 2012 strip would mark Life in Hell's conclusion. After Groening ended the strip, the Center for Cartoon Studies commissioned a poster that was presented to Groening in honor of his work. The poster contained tribute cartoons by 22 of Groening's cartoonist friends who were influenced by Life in Hell.

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