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She was born on January 24, 1911 in Indianapolis, Indiana. She was chronically ill as a child and spent much of her time reading literature of the fantastic. She left college during The Great Depression to work as a secretary at the Fletcher Trust Company in Indianapolis. Her first stories appeared in pulp magazines in the 1930s, including two significant series in Weird Tales.

One series concerns the rogue and adventurer, Northwest Smith, and his wanderings through the Solar System; the other is a short fantasy series about Jirel of Joiry (one of the first female protagonists in sword-and-sorcery fiction).

The most famous of the Northwest Smith stories is "Shambleau", which marked Moore’s first professional sale. It appeared in the magazine in November 1933, with the sale netting her a hundred dollars.

The first and most famous of the Jirel of Joiry stories is "Black God’s Kiss", which received the cover illustration (painted by Margaret Brundage) in the October 1934 Weird Tales. Her early stories were notable for their emphasis on the senses and emotions, which was highly unusual at the time.

Moore's work also appeared in Astounding Science Fiction magazine throughout the 1940s. Several stories written for that magazine were later collected in her first published book, Judgment Night, published by Gnome Press in 1952.

Included in that collection were “Judgment Night” (first published in August and September, 1943), the lush rendering of a future galactic empire with a sober meditation on the nature of power and its inevitable loss; “The Code” (July, 1945), an homage to the classic Faust with modern theories and Lovecraftian dread; “Promised Land” (February, 1950) and “Heir Apparent” (July, 1950) both documenting the grim twisting that mankind must undergo in order to spread into the solar system; and “Paradise Street” (September, 1950), a futuristic take on the Old West conflict between lone hunter and wilderness-taming settlers.

Moore met Henry Kuttner, also a science fiction writer, in 1936 when he wrote her a fan letter (mistakenly thinking that "C. L. Moore" was a man), and they married in 1940.

Afterwards, almost all of their stories were written in collaboration under various pseudonyms, most commonly “Lewis Padgett”. (Another pseudonym, one Moore often employed for works that involved little or no collaboration, was "Lawrence O’Donnell".)

In this very prolific partnership they managed to combine Moore's style with Kuttner's more cerebral storytelling. Their stories include the classic "Mimsy were the Borogoves" (the basis for the film The Last Mimzy) and "Vintage Season".

They also collaborated on a story that combined Moore’s signature characters, Northwest Smith and Jirel of Joiry: "Quest of the Starstone" (1937).

After Kuttner's death in 1958, Moore wrote almost no fiction and taught his writing course at the University of Southern California. She did write for a few television shows under her married name, but upon marrying Thomas Reggie (who was not a writer) in 1963, she ceased writing entirely.

C. L. Moore died on April 4, 1987 at her home in Hollywood, California after a long battle with Alzheimer's disease.