Using genetic and pharmacological approaches, we demonstrate that both RARγ/RXRα heterodimers involved in repression events, as well as PPARβ(δ)/RXRα heterodimers involved in activation events, are cell-autonomously required in suprabasal keratinocytes for the generation of lamellar granules (LG), the organelles instrumental to the formation of the skin permeability barrier. In activating PPARβ(δ)/RXRα heterodimers, RXRα is transcriptionally active as its AF-2 activation function is required and can be inhibited by an RXR-selective antagonist. Within repressing RARγ/RXRα heterodimers, induction of the transcriptional activity of RXRα is subordinated to the addition of an agonistic ligand for RARγ. Thus, the ligand that possibly binds and activates RXRα heterodimerized with PPARβ(δ) cannot be a retinoic acid, as it would also bind RARγ and relieve the RARγ-mediated repression, thereby yielding abnormal LGs. Our data also demonstrate for the first time that subordination of RXR transcriptional activity to that of its RAR partner plays a crucial role in vivo, because it allows RXRs to act concomitantly, within the same cell, as heterodimerization partners for repression, as well as for activation events in which they are transcriptionally active.