Prostate cancer (PCa) is the most common form of cancer in men in the developed world and the second leading cause of cancer-related deaths. While advanced PCa is initially controlled with hormonal therapies targeting the androgen receptor (AR) pathway, recurrence occurs because of the emergence of lethal castration-resistant PCa (CRPC). Despite newer AR pathway inhibitors that prolong survival, resistance still emerges, most often with rising PSA levels indicative of AR-driven activity, but increasingly as non-AR-driven cancer. Treatment resistance mechanisms include AR-signalling pathway alterations, AR-signalling bypass mechanisms, and AR-independent clonal evolution. The latter mechanism can lead to the emergence of neuroendocrine prostate cancer (NEPC), an aggressive lethal subtype of PCa. The incidence of treatment-induced NEPC is rising because of the widespread use of more potent AR pathway inhibitors. This comprehensive review of major NEPC drivers and facilitators defines three coordinated processes contributing to NEPC progression. Specifically, castration-resistant adenocarcinoma cells gain lineage plasticity under selective pressures of potent AR suppression to transform into AR-independent tumour cells. In concert, neuroendocrine (NE)-specific transdifferentiation factors induce NE lineage of these PCa cells, which, with support of increased proliferation factors, contributes to clonal expansion and tumour repopulation into NEPC. We examine the roles of each of the major NEPC contributors during the disease progression and identify potential therapeutic opportunities for targeted therapies.