Most of the conventional adenocarcinomas of the prostate display focal neuroendocrine (NE) differentiation at diagnosis, usually revealed by immunohistochemistry as solitary or clusters of cells, in the context of predominantly exocrine tumors. Even though the biological and clinical significance of NE differentiation in prostate cancer is still to be elucidated, NE phenotype is emerging as an important factor in the prognosis, evolution and progression of prostate cancer. It seems to be particularly relevant in facilitating prostate cancer progression during the ordinary androgen-suppression therapy (LHRH-analogs +/- anti-androgens). Several mechanisms have been identified: NE cells are androgen receptor negative, therefore they survive to androgen deprivation; NE cells produce peptides, hormones and growth factors which could stimulate proliferation [chromogranin (A-CgA), PTHrp, bombesin, etc.], inhibit apoptosis (Survivin) and stimulate neoangiogenesis [vascular endothelial GF (VEGF)] of the neighbouring exocrine prostate cancer cells. NE differentiation appears to be a dynamic phenomenon. The NE phenotype expression increases during androgen-deprivation therapy and results more elevated in hormone refractory than in hormone sensitive disease. Pre-clinical and clinical studies demonstrated a direct stimulation of NE differentiation by androgen-suppression therapy, resulting in a dramatic increase in the number of cells expressing NE markers. CgA appears to be the most sensitive marker and is most frequently used for detecting NE phenotype either at the tissue level or in the general circulation. Elevated plasma CgA levels are frequently observed in hormone-refractory disease and correlate with poor prognosis. Even in hormone refractory disease, NE differentiation is a time-dependent phenomenon and is not influenced by conventional antineoplastic treatments.