The Smyd gene family code for proteins containing a conserved core consisting of a SET domain interrupted by a MYND zinc finger. Smyd proteins are important in epigenetic control of development and carcinogenesis, through posttranslational modifications in histones and other proteins. Previous reports indicated that the Smyd family is quite variable in metazoans, so a rigorous phylogenetic reconstruction of this complex gene family is of central importance to understand its evolutionary history and functional diversification or conservation. We have performed a phylogenetic analysis of Smyd protein sequences, and our results show that the extant metazoan Smyd genes can be classified in three main classes, Smyd3 (which includes chordate-specific Smyd1 and Smyd2 genes), Smyd4 and Smyd5. In addition, there is an arthropod-specific class, SmydA. While the evolutionary history of the Smyd3 and Smyd5 classes is relatively simple, the Smyd4 class has suffered several events of gene loss, gene duplication and lineage-specific expansions in the animal phyla included in our analysis. A more specific study of the four Smyd4 genes in Drosophila melanogaster shows that they are not redundant, since their patterns of expression are different and knock-down of individual genes can have dramatic phenotypes despite the presence of the other family members.