Since Milstein’s discovery of CD1 in 1986, it was proposed that CD1 is an ancient class I molecule, perhaps predating the emergence of classical class I and class II. It was further proposed, by Kasahara and colleagues, that CD1’s presence on human chromosome 1, in a potential MHC paralogue, was a consequence of genome-wide duplications (2R hypothesis) at the dawn of vertebrate history. Our analysis of MHC paralogous regions in many vertebrates, and focusing on the amphibian Xenopus paralogous regions, shows that CD1’s presence on human chromosome 1 is not a consequence of 2R, rather a translocation from the bona fide MHC early in the evolution of mammals. A bevy of other immune genes, such as FcR and SLAM, were also part of this translocation. This new idea is consistent with CD1’s presence in the MHC-proper of some birds and reptiles. Although CD1’s location on human chromosome 1 is not a consequence of 2R, it is indeed ancient, probably having arisen after 1R (the first genome-wide duplication) in the proto MHC, based on CD1’s presence on a true paralogous region (chr 19) in reptiles. Furthermore, we have found other class I molecules encoded in this paralogous region (chr 19) in amphibians, reptiles, and mammals, also consistent with class I’s early emergence. In summary, CD1 arose early in evolution in the proto MHC, but seems to have been lost in fish and amphibians, its function perhaps assumed by other nonclassical class I molecules in these taxa. The data also suggest that both classical and nonclassical class I genes predated the emergence of class II in evolution.