The TRAP/SMCC/Mediator complex is a mammalian transcriptional regulatory complex that contains over 25 polypeptides and is, in part, phylogenetically conserved. It was originally isolated as a thyroid hormone receptor (TR)-associated protein (TRAP) complex that mediates TR-activated transcription from DNA templates in conjunction with the general transcription machinery, and probably acts in vivo after the action of other receptor-interacting coactivators involved in chromatin remodeling. Subsequently, the TRAP complex was identified as a more broadly used coactivator complex for a wide variety of activators. The TRAP220 subunit mediates ligand-dependent interactions of the complex with TR and other nuclear receptors; and genetic ablation of murine TRAP220 has revealed that it is essential both for optimal TR function and for a variety of early developmental and adult homeostasis events in mice, but not for cell viability per se.