Abstract: Androgen receptor (AR) addiction is the driving force behind the development of castrate resistant prostate cancer (CRPC). The recent development of second-generation high affinity antiandrogens, that once again will inhibit tumor growth in CRPC patients, validates that the AR pathway is still a central target for drug therapy. However, the inevitable failure of patients to these new antiandrogens indicates that more durable response with a comprehensive strategy to destroy tumor growth is needed. Using both genetically engineered mice and xenograft models, we have deciphered critical pathways that control prostate tumor progression. We have shown that prostate cancer cells undergo neuroendocrine differentiation (NED) via the wnt-signaling pathway. These NED cells, that commonly appear in advance human metastatic tumors, produce growth factors that stimulate growth of the adenocarcinoma by activating the NF-kappa B pathway. Activation of NF-kappa B in the tumor result in both increased metastasis and increased levels of AR that results in CRPC. Using these mouse models, we are developing new approaches to treat patients with CRPC.