As prostate cancer morbidity and mortality remain continuously high, there is an increasing need to elucidate the molecular mechanisms underlying the extensive heterogeneity and therapy resistance observed. Although initially effective, therapies that target the androgen receptor (AR) pathway are ultimately overcome in the majority of prostate tumors. Tumor heterogeneity contributes in part to this problem of resistance, and a lack of knowledge regarding the mechanisms that drive each tumor subtype remains a barrier to implementing effective secondary therapeutic strategies. Understanding subtype-specific mechanisms that drive initial tumor development as well as resistance is essential to improving disease outcomes. This thesis investigates the role of a prevalent genetic lesion observed in prostate tumors, fusion of transmembrane protease, serine 2 (TMPRSS2) gene with E26 transformation specific (ETS) related gene (ERG), known as the TMPRSS2-ERG fusion, in prostate tumorigenesis, progression, and therapy resistance. The studies reported here encompass analyses of human patient tumor samples, characterization of novel mouse models of prostate cancer, and functional analyses in human prostate cancer cell lines. We identify bromodomain containing protein 4 (BRD4) as a novel ERG cofactor that interacts in an acetylation-dependent manner with a prevalent prostate cancer-associated ERG variant to promote prostate cell invasion. We also define a mechanism of ERG-mediated transcriptional downregulation of a subset of cell cycle genes that ultimately prevents phosphatase and tensin homology (PTEN) and tumor protein p53 (TP53)-alteration induced lineage plasticity and antiandrogen therapy resistance, an effect mediated through the retinoblastoma (RB)/E2F1 pathway. Lastly, we show that ERG cooperates with an additional genetic alteration, gain of function mutant p53, to establish an aberrant transcriptional state that ultimately drives prostate tumorigenesis. Collectively, this work significantly advances our understanding of prostate tumor heterogeneity and reveals multiple potential therapeutic avenues specific to ERG-positive prostate tumors.