While in Paris, Hans's animal drawings came to the attention of a French publisher, who commissioned him to write a children's book. The result, Cecily G. and the Nine Monkeys, is little remembered today, but one of its characters, an adorably impish monkey named Curious George, was such a success that the couple considered writing a book just about him. Their work was interrupted with the outbreak of World War II. As Jews, the Reys decided to flee Paris before the Nazis seized the city. Hans built two bicycles, and they fled Paris just a few hours before it fell. Among the meager possessions they brought with them was the illustrated manuscript of Curious George.

The Reys' odyssey brought them to the Spanish border, where they bought train tickets to Lisbon. From there they returned to Brazil, where they had met five years earlier, but this time they continued to New York. The books were published by Houghton Mifflin in 1941. Hans and Margret originally planned to use watercolor illustration, but since they were responsible for the color separation, he changed these to the cartoon-like images that continue to feature in each of the books. (A collector's edition with the original watercolors has since been released.)

Curious George was an instant success, and the Reys were commissioned to write more adventures of the mischievous monkey and his friend, the Man in the Yellow Hat. They wrote seven stories in all, with Hans mainly doing the illustrations and Margret working mostly on the stories, though they both admitted to sharing the work and cooperating fully in every stage of development. At first, however, Margret's name was left off the cover, ostensibly because there was a glut of women already writing children's fiction. In later editions, this was changed, and Margret now receives full credit for her role in developing the stories.

The Reys relocated to Cambridge, Massachusetts during 1963, in a house near Harvard Square. Hans lived there until his death.A children's bookstore named Curious George & Friends (formerly Curious George Goes To Wordsworth) operates nearby in the Square.

Before the 1952 publication of Rey's The Stars: A New Way to See Them, (ISBN 0-395-24830-2) star charts used a conventional set of diagrams that were difficult to remember and relied on dim stars that are difficult to see in modern populated areas. Rey invented a new set of constellation diagrams that could be seen as cartoonish depictions of the creature or character the constellations was supposed to represent...- or, at least, were memorable. His constellation diagrams were adopted widely and now appear in many astronomy guides, such as Menzel's A Field Guide to the Stars and Planets. As of 2003 The Stars: A New Way to See Them, and a simplified presentation for children called Find the Constellations, are still in print. A new edition of Find the Constellations was released in 2008, updated with modern fonts, the new status of Pluto, and some more current measurements of planetary sizes and orbital radii.

Dr. Lena Y. de Grummond, a professor in the field of library science (specializing in children's literature) at The University of Southern Mississippi in Hattiesburg, Miss. contacted the Reys in 1966 about the university's new children's literature collection. H.A. and Margret made a donation of a pair of sketches at the time. In 1996, after Margret's death, it was revealed in her will that the entire literary estate of the Reys were to be donated to the de Grummond Children's Literature Collection at Southern Mississippi.