A variety of coregulator proteins serve as partners for nuclear receptors orchestrating the molecular events required for receptor-dependent transcriptional regulation. Some coregulators directly interact with nuclear receptors and provide a platform for recruitment of other factors that provide distinct biochemical activities that influence transcriptional efficiency. Coregulators can influence chromatin structure and activity via direct modification of histone proteins or by facilitating ATP-dependent chromatin remodeling. They also have the capacity to impact multiple steps in the transcription process including initiation, elongation, and mRNA splicing. Genetic analysis in humans and animal models are revealing the important cell and tissue-type specific actions of nuclear receptor coregulators as well and their role in human physiology and disease.