Recently, a number of genes have been identified that are associated with a failure of human sex determination, including WT1, DAX-1, SOX9, ATRX, and the Y-linked testis determination gene, SRY. Most cases of human sex reversal, XY females and XX males, do not, however, appear to be caused by mutations in these genes. This review highlights recent advances in this field and discusses the prospects of identifying genes in the sex-determining pathway.