Prostate cancer (PC) is the most frequently diagnosed cancer and the second leading cause of cancer-related death in men in the Western society. Unfortunatelyalthough the vast majority of patients are initially responsive to androgen-deprivation therapy (ADT)most cases eventually develop from hormone-sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). The main reason is PC heterogeneity and evolution during therapy. PC evolution is a continuously progressive process with combination of genomic alterations including canonical ARTMPRSS2-ERG fusionSPOP/FOXA1TP53/RB1/PTENBRCA2. Meanwhilesignaling pathways including PI3KWNT/β-cateninSRCIL-6/STAT3 are activatedto promote epithelial mesenchymal transition (EMT)cancer stem cell (CSC)-like features/stemness and neuroendocrine differentiation (NED) of PC. These improve our understanding of the genotype-phenotype relationships. The identification of canonical genetic alterations and signaling pathway activation in PC has shed more insight into genetic backgroundmolecular subtype and disease landscape of PC evolutionresulting in a more flexible role of individual therapies targeting diverse genotype and phenotype presentation.