It has become increasingly clear over the course of the past decade that the immune system genes of teleosts and tetrapods are plainly derived from common ancestral genes. The last 5 years, however, have also made it abundantly clear that in the teleost genome some of these genes are organized in a manner very different from that seen in mammals. These differences are probably the result of differences in life history traits, such as fecundancy, within each group of species when faced with an evolutionary fork in the road shortly after their divergence from each other. One group, the tetrapods, including mammals, chose a highly organized linked major histocompatibility complex, while in teleosts the major histocompatibility genes remained unlinked. In this review we will discuss the structural and functional implications of this different organization, particularly for major histocompatibility genes, but drawing on the current knowledge of some other genes for further support for the hypothesis that each group took a different road, one more traveled and one less taken.