Atypical clinical features in men with prostate cancer-such as clinical evidence of disease progression in the absence of a proportional increase in serum prostate-specific antigen level, bulky symptomatic tumor masses, exclusive visceral metastases, or a predominance of lytic bone metastases-should alert the clinician that an aggressive prostate cancer variant is present or emerging. Aggressive variants of prostate cancer often take the form of neuroendocrine or small-cell carcinomas, which frequently lack androgen receptor expression and respond poorly to hormonal therapies. Indeed, the finding of neuroendocrine or small-cell prostate carcinoma indicates the need for multimodality treatments that incorporate early combination chemotherapy and locoregional control of bulky tumor deposits, including untreated or recurrent primaries. As we learn to recognize this prostate cancer variant more often, we are reminded that not all prostate cancers share the same biology and that the androgen receptor is not the sole driver of this disease.