Members of the nuclear receptor family, the retinoic acid receptors (RARs) alpha, beta, and gamma, regulate cell differentiation and epigenetic states of stem and differentiated cells. We showed that these RARs also play key roles in cancer prevention and in the inhibition of diabetes and hepatic steatosis, but the complexity of signaling by multiple receptors and the regulated production of active ligands make it challenging to establish the molecular mechanisms for these effects. To develop new pharmacological treatments, we generated unique murine models of early stage clear cell renal cell carcinoma (ccRCC) and head and neck cancer (HNSCC). These models reflect molecular and histological changes that occur in human carcinogenesis, providing us with powerful systems in which to test new drugs and increase our understanding of the early stages of carcinogenesis. In our HNSCC model, we are analyzing retinoic acid receptor (RAR) gamma as a tumor suppressor, and we've shown that a RAR gamma selective agonist inhibits the development of oral squamous cell carcinoma. In our ccRCC model we've found novel therapeutic targets. Using both dietary (i.e., high fat diet) and genetic (i.e., db/db mice) models of diabetes and/or hepatic steatosis, we showed that a RAR beta selective retinoid can reduce the pathological features of diabetes and hepatic steatosis. Furthermore, we reported that this RAR beta selective retinoid is useful in treatment of diabetic nephropathy and is cardioprotective. Thus, combining pharmacological studies with representative disease models provides important insights into many common human diseases (metabolic syndrome, cancer, kidney disease, and heart disease), and can lead to new therapeutics to improve human health.