Despite improvements in diagnosis and treatment approaches, prostate cancer (PC) remains a leading cause of cancer-related death in men. PC progresses through various stages, mostly driven by androgen receptor signaling. However, after androgen deprivation therapies, in a significant portion of patients, several different molecular mechanisms contribute to the development of castration resistance. Delving deeply into the molecular landscape of castration-resistant PC, grasping the selective pressures exerted by therapies, and understanding the drivers of lineage plasticity is pivotal to prevent progression. Targeting genetic and epigenetic alterations that drive this transition will guide clinical management strategies and possibly prevent and/or treat lethal disease.