Neuroendocrine (NE) cells are a distinct epithelial cell compartment of the normal human prostate gland. Their phenotype and range of endocrine secretion products are similar, but not identical to those of NE-like cells from prostate carcinoma. Neuroendocrine differentiation (NED) is a feature commonly seen in prostate carcinoma and a number of studies pointed out that its extent is associated to hormone therapy refractory and aggressive disease. However, less information is available on the significance of NED in organ-confined prostate cancer, although identification of early predictors of aggressive disease would obviously allow for more adequate therapy. We review here recent advances in understanding the differentiation pathways of normal and malignant neuroendocrine cells as well as current information regarding the prognostic and therapeutic implication of NED assessment.