To be biologically active, proteins must adopt specific folded three-dimensional tertiary structures. Yet the genetic information for the proteins specifies only the primary structure, the linear sequence of amino acids in the polypeptide backbone. Many purified proteins can spontaneously refold in vitro after being completely unfolded, so the three-dimensional structure must be determined by the primary structure. How this occurs has become known as the protein-folding problem. It was primarily of academic interest, but the advent of protein engineering and the ability to produce any protein, often in an insoluble, unfolded, inactive and useless form, has made it also of great practical importance. The problem can be divided into two main questions. The first is by what kinetic process or pathway does protein adopt its native and biologically active folded conformation and the other, what is the physical basis of the stability of folded conformations. The present review summarizes the present state of knowledge of the problem and attempts to put it into perspective for what could follows.