Nuclear receptors (NRs) regulate the expression of target genes in response to activation by steroid hormones and other ligands, as well as a variety of other signaling pathways. NR coactivators are defined as cellular factors recruited by activated NRs that complement their function as mediators of the cellular response to endocrine signals. In this review, we will focus upon advances in our understanding of the function of coactivators as their characterization has progressed from mechanistic studies to an exploration of their biological roles in living animals.