This manuscript presents the first extensive phylogenetics analysis of a key family of immune regulators, the interferon regulatory factor (IRF) family. The IRF family encodes transcription factors that play important roles in immune defense, stress responses, reproduction, development, and carcinogenesis. Several times during their evolution, the IRF genes have undergone expansion and diversification. These genes were also completely lost on two separate occasions in large groups of metazoans. The origin of the IRF family coincides with the appearance of multicellularity in animals. IRF genes are present in all principal metazoan groups, including sea sponges, placozoans, comb jellies, cnidarians, and bilaterians. Although the number of IRF family members does not exceed two in sponges and placozoans, this number reached five in cnidarians. At least four additional independent expansions lead up to 11 members in different groups of bilaterians. In contrast, the IRF genes either disappeared or mutated beyond recognition in roundworms and insects, the two groups that include most of the metazoan species. The IRF family separated very early into two branches ultimately leading to vertebrate IRF1 and IRF4 supergroups (SGs). Genes encoding the IRF-SGs are present in all bilaterians and cnidarians. The evolution of vertebrate IRF family members further proceeded with at least two additional steps. First, close to the appearance of the first vertebrate, the IRF family probably expanded to four family members, predecessors of the four vertebrate IRF groups (IRF1, 3, 4, 5 groups). In the second step, 10 vertebrate family members evolved from these four genes, likely as a result of the 2-fold duplication of the entire genome. Interestingly, the IRF family coevolved with the Rel/NF-kappaB family with which it shares some important evolutionary characteristics, including roles in defense responses, metazoan specificity, extensive diversification in vertebrates, and elimination of all family members in nematodes.