Prostate cancer (PCa) is a major health risk for older men worldwide.Existing systemic therapies mostly target androgen receptor (AR).Although treatments are initially effective,the disease always recurs.A potential mechanism for the treatment failure is that PCa contains,in addition to the AR-positive luminal type tumor cells,a small component of neuroendocrine (NE) cells.The function of NE cells in PCa remains poorly understood,and one important characteristic of these cells is their lack of expression of AR and resistance to hormonal therapy.In addition,many patients develop the more aggressive small-cell neuroendocrine carcinoma (SCNC) after hormonal therapy.Although this clinical phenomenon of disease transformation from adenocarcinoma to SCNC is well established,the cell of origin for SCNC remains unclear.Recently,loss of function of Rb and TP53 and amplification and overexpression of MYCN and Aurora A kinase have been identified as important biomarkers and potential disease drivers.In this article,we systematically review the histology of normal prostate and prostate cancer including the main histologic types:adenocarcinoma and SCNC.We also review the findings from many studies using cellular and animal models as well as human specimens that attempt to understand the molecular mechanisms of treatment failure,disease progression,and tumor transformation from adenocarcinoma to SCNC.