Previously assumed to be rare, the prevalence of aggressive variants of prostate cancer has increased rapidly. This histologically heterogeneous group of cancers, including different forms of the neuroendocrine carcinoma of the prostate, share a common clinical course associated with a poor response to androgen deprivation treatment and fatal prognosis. Currently, the most commonly used terms are aggressive variant of prostate cancer and treatment-related neuroendocrine prostate cancer. The best treatment of these tumors in clinical routine is still being debated. Here, we highlight the clinically most relevant aspects of this heterogeneous disease and summarize recommendations for clinical routine.