Humans are faced with a vast number of pathological conditions. Some the most prevalent and deadly disease states include cancer, obesity, and diabetes. A large amount of scientific research and development has gone into determining the underlying cause of these pathologies. Certain aspects of the aforementioned diseases have been linked to the aberrant expression and activity of selected gene-expression-programs. Gene expression is regulated by proteins known as transcription factors. One of the largest transcription factor families is the nuclear receptor (NR) superfamily. The ability of NRs to drive gene activation is directed by specific interacting proteins called cofactors. This review will highlight new discoveries regarding the mechanistic role of NRs and their associated protein cofactors in regulating gene activation and in the progression of cancer, diabetes, and obesity.