A parody of the political ideologies of the Cold War, the strip was created by Cuban expatriate cartoonist Antonio Prohías, and debuted in Mad #60, dated January 1961.

He fled to the United States on May 1, 1960, three days before Fidel Castro's government nationalized the last of the Cuban free press.

[4] Prohías cryptically signed each strip on its first panel with a sequence of Morse code characters that spell "BY PROHIAS".

In 1965, he began to experiment with not drawing frames on the spies' shades, and this became a consistent trait from late 1966 on, so that the characters' eyes appeared to have no sclera—just very large pupils, all black except for reflective glints.

But when a spy was caught in an explosion, sometimes his fully drawn shades would fly along with other items such as hats, boots, and dentures.

[4] After that he drew gag strips for the titles (such as one involving radioactive waste in #287) and wrote several stories for Clarke or Manak to draw, with his last such contribution in #337 (July 1995).

In 2001, Kuper began drawing it in full color when the magazine made its switch from black and white art.

With Mad reverting to a reprint format, Kuper's second-to-last Spy strip appeared in issue #18 (the magazine had moved to Burbank, California in 2018, adopting new numbering starting with #1).

The Spies were modeled after El Hombre Siniestro ("The Sinister Man"), a character Prohías created in the Cuban magazine Bohemia in 1956.

Prohías described the character as someone who "thought nothing of chopping the tails off of dogs, or even the legs off of little girls" and stated he was "born out of the national psychosis of the Cuban people.

"[4] 'El Hombre Siniestro bore a strong resemblance to the Spies—although, instead of fighting against a set rival, he simply does horrible things to anyone he can find.