The limits and relationships of serranid and percid fishes, in the context of the percomorph radiation, were resolved using 4036 aligned base pairs of mitochondrial and nuclear DNA sequence data for 180 acanthomorph species. Representatives of all major serranid and percid lineages were analyzed along with 91 additional families from six acanthomorph orders and 25 suborders. Percidae was recovered as monophyletic, and the traditional Serranidae was recovered as polyphyletic, forming five clades: Niphon, Acanthistius, Epinephelinae (less Niphon), Anthiinae (less Acanthistius and Zalanthias kelloggi [formerly included in Plectranthias]), Serraninae (including Zalanthias kelloggi). These traditional “percoid” families were separated from all other “percoid” taxa and recovered within a clade composed of the mail-cheeked fishes and their allies. Based on the evidence provided in this molecular study and prior morphological studies, we recommend taxonomic changes to the Perciformes, Percoidei, Trachinoidei, and Serranidae, we resurrect the Epinephelidae and Niphonidae, and we create a new group, the Moronoidei, to reflect our recovered relationships.