Professor Smale spent the main part of his career at the University of California, Berkeley. He was awarded the Fields Medal in 1966. He retired from UC Berkeley in 1995, moving to a professorship at the City University of Hong Kong. In 2007 he was awarded the Wolf Prize in Mathematics. He is one of only twelve Fields Medalists to win both prizes. Since 2009 he has been a University Distinguished Professor at the City University of Hong Kong.

In 1998 Professor Smale compiled a list of 18 problems in mathematics to be solved in the 21st century, known as Smale's problems. The list was created in the spirit of Hilbert's famous list of problems produced in 1900. In fact, Smale's list contains some of the original Hilbert problems, including the Riemann hypothesis and the second half of Hilbert's sixteenth problem, both of which are still unsolved. Other famous problems on his list include the Poincaré conjecture, which has recently been solved by Grigori Perelman, the P = NP problem, and the Navier-Stokes equations, all of which have been designated Millennium Prize Problems by the Clay Mathematics Institute.