Nature's Way, the precursor to The Far Side first appeared in the Seattle Times in 1979. After Larson’s success with the San Francisco Chronicle, The Far Side was syndicated in 1980 by Chronicle Features. Its first appearance in the Chronicle was on January 1, 1980. It ran for 15 years until Larson retired with his final strip published on January 1, 1995. Larson thought the series was getting repetitive and did not want to enter what he called the "Graveyard of Mediocre Cartoons."
Themes in The Far Side were often surreal, such as “How cows behave when no human watches” or "The unexpected dangers of being an insect." Often, the behavior of supposedly superior humans was compared with animals: surrounded by fences and dense housing, a father explains to his son that a bird song is a territorial marking common to the lower animals. Animals and other creatures were frequently presented anthropomorphically. For example, one strip depicts a family of spiders driving in a car with a "Have a Nice Day" bumper sticker, featuring a "smiley face" with eight eyes.
One of Larson's more famous cartoons shows a chimpanzee couple grooming. The female finds a blonde human hair on the male and inquires, "Conducting a little more 'research' with that Jane Goodall tramp?" The Jane Goodall Institute thought this was in bad taste, and had their lawyers draft a letter to Larson and his distribution syndicate, in which they described the cartoon as an "atrocity". They were stymied by Goodall herself, who was in Africa at the time, when she returned and saw the cartoon. She stated that she found the cartoon amusing, and later personally met Larson. Since then, all profits from sales of a shirt featuring this cartoon go to the Goodall Institute.
Goodall wrote a preface to The Far Side Gallery 5, detailing her version of the "Jane Goodall Tramp" controversy. She praised Larson's creative ideas, which often compare and contrast the behavior of humans and animals. In 1988, Larson visited Gombe Streams National Park and was attacked by Frodo, a chimp described by Goodall as a "bully." Larson escaped with cuts and bruises.
Larson's Far Side cartoons were syndicated worldwide and published in many collections. They were reproduced extensively on greeting cards, which were very popular; however, they were discontinued in March 2009. Two animated versions, "Tales from the Far Side" and "Tales from the Far Side II", were produced for television in 1994 and 1997, respectively.
Larson published a 2007 calendar with all author royalties donated to Conservation International.
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