The species in the repleta group of the genus Drosophila have been placed into five subgroups-the mulleri, hydei, mercatorum, repleta, and fasciola subgroups. Each subgroup has been further subdivided into complexes and clusters. Extensive morphological and cytological analyses of the members of this species group have formed the foundation for the proposed relationships among the members of the repleta species group. Fifty-four taxa, including 46 taxa belonging to the repleta species group, were sequenced for fragments of four genes-16S ribosomal DNA (16S), cytochrome oxidase II (COII), and nitrogen dehydrogenase 1 (ND1) of the mitochondrial genome and a region of the hunchback (hb) nuclear gene. We also generated a partial data set of elongation factor 1-alpha (Ef1alpha) sequences for a subset of taxa. Our analysis used both DNA characters and chromosomal inversion data. The phylogenetic hypothesis we obtained supports many of the traditionally accepted clades within the mulleri subgroup, but the monophyly of taxonomic groups outside of this subgroup appears not to be supported. Phylogenetic analysis revealed one well-supported, highly resolved clade that consists of closely related members of the mulleri and buzzatii complexes. The remaining taxa, a wide assortment of taxonomic groups, ranging from members of other species groups to members of several subgroups and members of three species complexes from the mulleri subgroup are found in poorly supported arrangements at the base of the tree.