Prostate cancer (PCa) is the second most common malignancy in men and represents about 7% of newly diagnosed tumors worldwide (and up to 15% in developed countries). At the genomic level, PCa is generally characterized by copy number alterations and/or gene structural rearrangements that encompass multiple genes, including oncogenes such as ERG and MYC and tumor suppressor genes such as TP53 and PTEN. To advance our understanding of the role of specific genomic alterations in PCa, genetically engineered mouse models (GEMMs) have been pivotal in complementing large-scale human sequencing initiatives. In this Review, we focus on the main altered genes in PCa and how they have been modeled in different GEMMs to study the molecular mechanisms underlying PCa tumorigenesis and progression.