We describe here the analysis of congenital malformations in compound mutant fetuses bearing null alleles in one RXR (α β or γ) and one RAR (α β or γ) isotype gene. A marked synergy was observed between the effects of mutations in RXRα and RARs, as a large number of developmental defects previously found mainly in RAR single and compound mutants were recapitulated in specific RXRα/RAR compound mutants. Several malformations were seen only in one type of RXRα/RAR mutant combination, whereas others were seen in several types of RXRα/RAR double mutants. No synergy was observed between the effects of mutations of either RXRβ or RXRγ mutations and those of any of the RAR mutations. These genetic data suggest that RXR/RAR heterodimers are the functional units transducing the retinoid signal for a large number of RA-dependent processes, and furthermore, that RXRα is the main RXR implicated in the developmental functions of RARs. The significance of these observations is discussed with respect to the problem of functional specificity and redundancy among retinoid receptors in vivo.