Our laboratory has a long-standing interest in understanding the relationship between the processes that control normal development and those that go awry in cancer, with primary interests in prostate and bladder cancer. Over the years, our laboratory has taken a multi-disciplinary approach to investigate mechanisms of cancer initiation and progression using in vivo mouse models. We have generated unique genetically-engineered mouse (GEM) models of prostate and bladder cancer that have provided novel insights into mechanisms of tumorigenesis and valuable pre-clinical models for analysis of new therapeutic approaches and mechanisms of drug resistance. Our GEM models of prostate cancer recapitulate the full spectrum of the disease, ranging from mildly dysplastic to fully metastatic. Similarly, our GEM models of invasive bladder cancer closely mimic the cellular and molecular features of the human disease. In our recent studies, we have been using systems biology approaches for cross-species analyses to integrate experimental data from mouse models and human cancer. Collectively, our studies have led to the development of promising new biomarkers that distinguish cancer subtypes, promising new treatments for intervention, and new ideas about mechanisms of disease resistance.