Wile E. has been trying to catch the elusive Road Runner for decades, but the Coyote's plans always seem to backfire.

Instead of his animal instincts, Wile E. uses a variety of mail-order products to capture the Road Runner. The word acme is derived from a Greek word meaning the peak, zenith or prime, but products from the fictional Acme Corporation are often generic, failure-prone, or explosive. In one of the later cartoons, it is revealed that ACME is "A Wholly-Owned Subsidiary Of Roadrunner Corporation."

Chuck Jones based the Coyote on Mark Twain's book Roughing It, in which Twain described the coyote as "a long, slim, sick and sorry-looking skeleton" that is "a living, breathing allegory of Want. He is always hungry."

In a 1975 issue of the Looney Tunes & Merrie Melodies comic book series Beep Beep The Road Runner, the Coyote becomes so obsessed with discovering his middle name that he starts interviewing coyote relatives who might know. His uncle Kraft E. Coyote is the one to spill the beans and tell him that his middle name is Ethelbert.

Fast and Furry-ous (1949) set the template for the series, in which Wile E. Coyote (here given the Latin name Carnivorous Vulgaris) tries to catch and eat the Road Runner (Accelleratii Incredibus) using a variety of mail-order products. In this first cartoon, not all of the products are yet made by ACME.

The first product that was actually labeled from ACME was a Super Suit, which Wile E. assumed would allow him to fly. It did not.

While he is usually silent in the regular Road Runner and Coyote shorts, Wile E. appears separately as an adversary of Bugs Bunny in five cartoons from 1952 to 1963: "Operation: Rabbit", "To Hare Is Human", "Rabbit's Feat", "Compressed Hare", and "Hare-Breadth Hurry". In these solo outings he speaks with a refined, ego-maniacal, almost English-sounding accent provided by Mel Blanc.

Gravity is Wile E. Coyote's worst enemy. Sometimes, after chasing the Road Runner over the edge of a cliff, Wile E. is allowed to hang in midair until he realizes that he is about to fall--a process that has been referred to elsewhere as Road-Runnering or a Wile E. Coyote moment. Gravity, of course, has no effect on the Road Runner.

The reason Ralph Wolf looks so familiar is that Chuck Jones used the Coyote's character design to create him. Like Wile E. in the Road Runner and Coyote series, Ralph has an appetite for doing things the hard way and orders products from the Acme Corporation in order to carry out his sheep-stealing schemes, but he lacks Wile E.'s fanaticism, forgetting all about the sheep and even exchanging pleasantries with Sam during lunch breaks and after they clock out for the day.

In Soup or Sonic (1980), Wile E. chases the Road Runner through a series of pipelines, which causes them to emerge in a greatly shrunken state. Realizing this, they re-enter the pipeline. The Road Runner emerges at normal size, but Wile E. is still tiny. Seeing this, the Road Runner stops and allows his rival to "catch" him. Staring up at the massive Road Runner, the Coyote can only hold up two signs to the audience stating, "Okay, wise guys, you always wanted me to catch him." and "Now what do I do?"