PCOS is a complex genetic disease resulting from the interplay between susceptibility genes and environmental factors. Hyperandrogenemia consistent with an alteration in ovarian and adrenal steroidogenesis is the major reproductive phenotype in families of women with PCOS, including mothers and brothers. Reproductive age sisters have two affected phenotypes: (1) hyperandrogenemia and chronic anovulation or (2) hyperandrogenemia with regular menses and apparently normal fertility. Menstrual regularity is a dichotomous trait in affected sisters suggesting that there may be a metabolic threshold for ovulation. We have now mapped a genetic variant conferring PCOS susceptibility to an allele of a dinucleotide repeat in intron 55 of the fibrillin-3 gene on chromosome 19p13.2 that is both linked and associated with the reproductive phenotype. The metabolic phenotypes of insulin resistance, metabolic syndrome and elevated LDL-cholesterol levels track with hyperandrogenemia. Further, the PCOS susceptibility allele is associated with several of these metabolic phenotypes in women with PCOS and their first-degree relatives. These observations suggest that reproductive and metabolic abnormalities are either causally related, have a common pathogenesis (e.g., same gene product), or result from genes within the same pathway. It is also possible that these abnormalities result from closely linked genes. In utero testosterone excess can reproduce many features of the PCOS reproductive and metabolic phenotypes in rodents, sheep and non-human primates. In women, androgens play an important role in sustaining gonadotropin secretory and metabolic defects of PCOS. Further, androgen excess is an early abnormality in girls at risk for PCOS. We propose that hyperandrogenemia resulting from variation in a gene(s) regulating steroidogenesis causes many of reproductive and metabolic features of PCOS by programming actions at critical periods of development as well as by ongoing actions in the adult. Additional environmental factors, such as obesity, modify these phenotypes.