BACKGROUND: Yponomeutoidea, one of the early-diverging lineages of ditrysian Lepidoptera, comprise about 1,800 species worldwide, including notable pests and insect-plant interaction models. Yponomeutoids were one of the earliest lepidopteran clades to evolve external feeding and to extensively colonize herbaceous angiosperms. Despite the group’s economic importance, and its value for tracing early lepidopteran evolution, the biodiversity and phylogeny of Yponomeutoidea have been relatively little studied. METHODOLOGY/PRINCIPAL FINDINGS: Eight nuclear genes (8 kb) were initially sequenced for 86 putative yponomeutoid species, spanning all previously recognized suprageneric groups, and 53 outgroups representing 22 families and 12 superfamilies. Eleven to 19 additional genes, yielding a total of 14.8 to 18.9 kb, were then sampled for a subset of taxa, including 28 yponomeutoids and 43 outgroups. Maximum likelihood analyses were conducted on data sets differing in numbers of genes, matrix completeness, inclusion/weighting of synonymous substitutions, and inclusion/exclusion of “rogue” taxa. Monophyly for Yponomeutoidea was supported very strongly when the 18 “rogue” taxa were excluded, and moderately otherwise. Results from different analyses are highly congruent and relationships within Yponomeutoidea are well supported overall. There is strong support overall for monophyly of families previously recognized on morphological grounds, including Yponomeutidae, Ypsolophidae, Plutellidae, Glyphipterigidae, Argyresthiidae, Attevidae, Praydidae, Heliodinidae, and Bedelliidae. We also assign family rank to Scythropiinae (Scythropiidae stat. rev.), which in our trees are strongly grouped with Bedelliidae, in contrast to all previous proposals. We present a working hypothesis of among-family relationships, and an informal higher classification. Host plant family associations of yponomeutoid subfamilies and families are non-random, but show no trends suggesting parallel phylogenesis. Our analyses suggest that previous characterizations of yponomeutoids as predominantly Holarctic were based on insufficient sampling. CONCLUSIONS/SIGNIFICANCE: We provide the first robust molecular phylogeny for Yponomeutoidea, together with a revised classification and new insights into their life history evolution and biogeography.