In this paper, the Clusiidae (Diptera: Schizophora) is analyzed phylogenetically using morphological and molecular data sets, and then redefined on the basis of derived morphological characters. The biology and distribution of the Clusiidae are also reviewed, a key is provided to the World genera, the status of the genus Craspedochaeta Czerny is reevaluated and the type of Heterochroa pictipennis Wulp is discussed. Molecular data sets include genomic DNA sequences from the mitochondrial genes COI (cytochrome oxidase subunit I) and COII (cytochrome oxidase subunit II), the large ribosomal nuclear subunit 28S, and the nuclear protein-coding carbomoylphosphate synthase (CPS) domain of CAD (or “rudimentary”). Genes were analyzed separately, in combination with each other, and in combination with a morphological data set. Although individual molecular data sets often provided conflicting phylogenetic signals, the topologies of the cladograms produced from each data set alone or in combination were largely similar. Most genus-level relationships and several basal divergences were unresolved, but Apiochaeta was very strongly and consistently supported as Sobarocephalinae, not Clusiinae. The Clusiinae and Sobarocephalinae are subsequently redefined using an adjusted morphological tree — retaining Apiochaeta in the Sobarocephalinae — that is only slightly longer (8.4%, or seven steps) than the most parsimonious tree. Our results illustrate the benefits of multiple independent data sets for phylogenetic reconstruction in order to verify and refine existing classifications.