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The Drosophila buzzatii cluster is a South American clade that encompasses seven closely related cactophilic species and constitutes a valuable model system for evolutionary research. Though the monophyly of the cluster is strongly supported by molecular, cytological and morphological evidence, phylogenetic relationships within it are still controversial. The phylogeny of the D. buzzatii cluster has been addressed using limited sets of molecular markers, namely a few nuclear and mitochondrial genes, and the sharing of fixed chromosomal inversions. However, analyses based on these data revealed inconsistencies across markers and resulted in poorly resolved basal branches. Here, we revise the phylogeny of the D. buzzatii cluster based on a large transcriptomic dataset of 813 kb obtained from four members of this cluster: D. antonietae, D. borborema, D. buzzatii and D. koepferae, using the close relative D. mojavensis (also a member of the repleta group) as outgroup. Our phylogenomic analyses confirm that D. buzzatii is sister to the other six members of the cluster and, though incomplete lineage sorting likely obstructs phylogenetic resolution among these six species, allowed us to recover a novel topology. Divergence time estimates date the radiation of the cluster to the recent upper Pleistocene with most speciation events compressed to the last 500,000 years.