In 1998 he constructed a list of 18 problems in mathematics to be solved in the 21st century. This list was compiled in the spirit of Hilbert's famous list of problems produced in 1900. In fact, Smale's list includes some of the original Hilbert problems. Smale's problems include the Jacobian conjecture and the Riemann hypothesis, both of which are still unsolved.

Stephen Smale is also famous for the proof of sphere eversion. That is, turning a sphere inside out without creating any crease.