AR gene mutations occur in both early-stage prostate cancers (28, 51, our unpublished data) and late-stage disease (36, 37, 55-57). One common feature is that both types of mutations retain ligand-dependent transcriptional activity. We speculate that AR mutations may characterize a more aggressive disease, or confer an ability to survive androgen ablation therapy. A large percentage of tumors appears to have no AR gene mutation, but the possibility has not been ruled out that tumors without an AR gene mutation may nonetheless produce variant AR, for example, by alternative splicing. The apparent absence of AR gene mutations in the majority of early-stage tumors indicates that the role of androgen in the development of clinical prostate cancer is mediated predominantly by a normal AR gene, which exists as multiple alleles that differ in glutamine and glycine repeat length, and that potentially differ in signal-transducing activity. Glutamine and glycine repeat length may thereby modulate the effect of androgen on tumor cell proliferation. The effect of glutamine and glycine repeat length on AR function may determine the sensitivity of tumor cells to existing tissue levels of dihydrotestosterone, but tissue dihydrotestosterone levels depend on circulating androgen levels and the amount of 5 alpha-reductase activity in the tissue. Therefore, although potential AR activity may be affected by the length of the glutamine and/or glycine repeat, actual AR activity will depend also on these other factors.