In higher eukaryotes, steroids/thyroid hormones and many lipophilic compounds regulate cellular physiology through binding to the steroid/nuclear receptor proteins. Steroid/nuclear receptors are ligand-dependent transcriptional activators that can stimulate gene expression. This transcriptional activation plays a pivotal role in hormone-regulated physiological and pharmacological responses. In recent years, several steroid/nuclear receptor cofactors have been identified and found to interact with the receptor and modulate its transcriptional activity. Among these cofactors, a family of three co-activators has been the focus of intense studies. Although gaps remain, progress has been made in understanding how a given co-activator interacts with the receptor and promotes transcriptional activation. We are beginning to understand co-activator action; for instance, several studies have established the molecular basis of antagonism by anti-hormones and the connection of co-activators with human cancers.