Combined loss of tumor suppressors (TSPs), PTEN, TP53, and RB1, is highly associated with small cell carcinoma of prostate phenotype. Recent genomic studies of human tumors as well as analyses in mouse genetic models have revealed a unique role for these TSPs in dictating epithelial lineage plasticity-a phenomenon that plays a critical role in the development of aggressive variant prostate cancer (PCa) and associated androgen therapy resistance.