Recent discoveries have changed our view of the evolutionary history of retinoic acid (RA) machinery. It is no longer considered a vertebrate or chordate invention but rather a common genetic toolkit of diverse lineages of metazoans. In particular, the basic machinery of RA-metabolizing enzymes, retinoid-binding proteins and RA-binding nuclear receptors has been identified in protostome and deuterostome lineages. Moreover, the retinoid content and the effects of RA treatment have been described in a number of invertebrates, although the physiological role of RA signaling outside vertebrates is still not fully understood. This review summarizes the evidence gathered over many years on the invertebrate RA system, highlighting the ancient origin of the RA genetic machinery and a basic role in neuronal differentiation. Comparison of invertebrate and vertebrate RA toolkits suggests some innovations in the RA machinery of vertebrates that might have contributed to improving the physiological control of retinoid homeostasis, compensating for vitamin A fluctuations in this lineage. Analysis of the RA machinery in invertebrates also reveals independent losses of RA components during evolution, which might be related to changes in embryonic developmental modes and the absence of the temporal collinearity of hox clusters. Additional studies analyzing the biochemical and functional characteristics of the invertebrate RA genetic machinery are warranted to lend experimental support to the hypotheses sketched in this review. These hypotheses open, however, new perspectives toward understanding how the RA genetic machinery evolved to suit the physiological and developmental requirements of metazoans.