Prostate cancer is one of the most common malignancies in men, with most cases initially responding to androgen deprivation therapy. However, a significant number of patients eventually develop castration-resistant prostate cancer, an aggressive form of the disease. Although androgen receptor (AR) pathway inhibitors target AR signaling, and have extended survival in patients with castration-resistant prostate cancer, prolonged treatment can lead to the emergence of neuroendocrine prostate cancer (NEPC), a lethal subtype characterized by the expression of neuroendocrine markers and reduced AR activity. The transition from adenocarcinoma to NEPC is driven by lineage plasticity, wherein cancer cells adopt a neuroendocrine phenotype to evade treatment. Consequently, NEPC patients face poor clinical outcomes and limited effective treatment options. To improve outcomes, it is crucial to understand the molecular mechanisms driving NEPC development. In this review, we highlight the role of transcription factors in this process and explore their potential as therapeutic targets.