Retinoid X receptors (RXRs) have been implicated in a diversity of cellular processes ranging from cellular proliferation to lipid metabolism. These pleiotropic effects stem not only from the ability of RXRs to dimerize with diverse nuclear receptors, which exert transcriptional control on specific aspects of cell biology, but also because binding of RXR ligands to heterodimers can stimulate transcriptional activation by RXR partner receptors. This signaling network is rendered more complex by the existence of different RXR isotypes (RXRα, RXRβ, RXRγ) with distinct properties that thereby modulate the transcriptional activity of RXR-containing heterodimers. This review discusses the emerging roles of RXR isotypes in the RXR signaling network and possible implications for our understanding of nuclear receptor biology and pharmacology.