Androgen-receptor (AR) gene mutations have been found in clinical prostate cancer, both prior to hormonal therapy and in hormone-refractory disease that persists despite androgen-ablative therapy. Thus, mutations that are present in late-stage disease might arise prior to therapy rather than as a result of therapy. A common feature of mutations in untreated prostate cancer and in hormone-refractory prostate cancer is that the AR retains activity as a ligand-dependent transcription factor. Some AR mutations in prostate cancer show broadened ligand specificity, such that the transcription-factor activity of the AR can be stimulated not just by dihydrotestosterone (DHT) but also by estradiol and other androgen metabolites that have a low affinity for the AR. The activation of mutant AR by estrogen and weak androgens could confer on prostate cancer cells an ability to survive testicular androgen ablation by allowing activation of the AR by adrenal androgens or exogenous estrogen. Such mutations might confer an advantage even prior to androgen ablation, since prostate cancer has lower levels of 5 alpha-reductase and, therefore, of DHT, than normal. Thus, AR mutations that occur prior to therapy may characterize a more aggressive disease. A large percentage of tumors appear to have no AR gene mutation. In tumors without an AR gene mutation, AR function might be affected via other mechanisms (e.g., AR gene amplification, which could increase the amount of AR activity at a given DHT level). Importantly, the apparent absence of AR gene mutations in the majority of earlystage tumors indicates that the role of androgen in the development of clinical prostate cancer is mediated predominantly by a normal AR gene. There are actually multiple alleles of the normal AR gene; these allelic variants differ in glutamine and glycine repeat length in the transactivation domain of the protein, and they may differ in signal-transducing activity. The glutamine and glycine repeat length may thereby modulate the effect of androgen on tumor-cell proliferation that occurs during clonal expansion.