The wood-warblers (family Parulidae) fall within a radiation of passerine birds commonly known as the New World nine-primaried oscines. Defining familial relationships within that radiation has previously been challenging because of its extremely high diversity, a paucity of phylogenetically informative morphological characters, and an apparent high rate of cladogenesis early in the radiation's history. Here, analyses of mitochondrial and nuclear DNA sequences demonstrate that the 25 extant genera traditionally placed in the Parulidae do not form a monophyletic group. Instead, all reconstructions identify a well-resolved clade of 19 genera (Vermivora, Parula, Dendroica, Catharopeza, Mniotilta, Setophaga, Protonotaria, Helmitheros, Limnothlypis, Seiurus, Oporornis, Geothlypis, Wilsonia, Cardellina, Ergaticus, Myioborus, Euthlypis, Basileuterus, and Phaeothlypis) that are all morphologically typical wood-warblers traditionally placed in the Parulidae. Six genera traditionally assigned to the Parulidae—Microligea, Teretistris, Zeledonia, Icteria, Granatellus, and Xenoligea—fall outside this highly supported clade in all mtDNA-based and nuclear DNA-based reconstructions, and each is probably more closely allied to taxa traditionally placed in other nine-primaried oscine families. The long, well-supported, and independently confirmed internode at the base of this wood-warbler clade provides the opportunity to define a monophyletic Parulidae using several complementary molecular phylogenetic criteria. Support for those relationships comes from reconstructions based on a range of nucleotide-intensive (from 894 to 3,638 nucleotides per taxon) and taxon-intensive (45 to 128 species) analyses of mtDNA sequences, as well as independent reconstructions based on nucleotide substitutions in the nuclear-encoded c-mos gene. Furthermore, the 19 typical wood-warbler genera share a synapomorphic one-codon c-mos deletion not found in other passerines. At a slightly deeper phylogenetic level, our mtDNA-based reconstructions are consistent with previous morphologic and genetic studies in suggesting that many nine-primaried oscine taxa have unanticipated affinities, that many lineages arose during an early and explosive period of cladogenesis, and that the generation of a robust nine-primaried oscine phylogeny will require robust taxonomic sampling and extensive phylogenetic information.