Summary: The molecules of the vertebrate immune system provide some of the best documented examples of natural selection acting at the molecular level. The major histocompatibility complex (MHC) molecules are a family of highly polymorphic loci whose products present peptides to T cells. Four distinct lines of evidence support the hypothesis that the natural selection acts to maintain MHC polymorphism: (1) evidence from the unusual allelic frequency distribution seen at MHC loci; (2) evidence from the pattern of nucleotide substitution at MHC loci, which shows an enhanced rate of nonsynonymous (amino acid-altering) substitution in the codons encoding the peptide-binding region of the molecules; (3) the existence of long-lasting polymorphisms at certain MHC loci; and (4) the fact that introns at MHC loci are homogenized by recombination and subsequent genetic drift. Certain other immune system gene families provide evidence that natural selection has acted to create diversity among family members. Examples include molecules of the specific immune system (such as immunoglobulin V region genes) and molecules of the innate immune system (such as defensins).