Born in Philadelphia, Santore graduated from the Philadelphia Museum School of Art (now the University of the Arts) in 1956. He began his career as a freelance illustrator working for advertising agencies and magazines including, TV Guide, Saturday Evening Post, Time, Life and many others. Since 1986 Santore has worked as a children's book illustrator becoming one of the most respected and acclaimed illustrators of today.
His work has been the focus of several major exhibitions at the Brandywine River Museum of Art and the Society of Illustrators in New York. He was also included in the nationwide traveling exhibition Myth, Magic and Mystery: One Hundred Years of American Children's Book Illustration. Santore is the recipient of numerous awards including the Society of Illustrators Award of Excellence and the Hamilton King Award. His work is in the permanent collections of the Museum of Modern Art, the Brandywine River Museum of Art, and the Free Library of Philadelphia.