Many proteins have been characterized as coregulators that can be recruited by DNA-binding nuclear receptors to influence transcriptional regulation. Recent genetic and biochemical studies have shown that cellular levels of coregulators are crucial for nuclear receptor-mediated transcription, and many coregulators have been shown to be targets for diverse intracellular signaling pathways and post-translational modifications. This review focuses on the different modes of regulation of nuclear receptor coregulators and the implications for tissue- and context-specific transcriptional responses to hormone and membrane receptor signaling.