We investigated rates of chromosomal evolution in Drosophila mojavensis using whole-genome sequence information from D. mojavensis, Drosophila buzzatii, and Drosophila virilis. Drosophila mojavensis is a cactophilic species of the repleta group living under extreme ecological conditions in the deserts of the Southwestern United States and Northwestern México. The genome of D. buzzatii, another member of the repleta group, was recently sequenced and the largest scaffolds anchored to all chromosomes using diverse procedures. Chromosome organization between D. mojavensis and D. buzzatii was compared using MUMmer and GRIMM software. Our results corroborate previous cytological analyses that indicated chromosome 2 differed between these 2 species by 10 inversions, chromosomes X and 5 differed by one inversion each, and chromosome 4 was homosequential. In contrast, we found that chromosome 3 differed by 5 inversions instead of the expected 2 that were previously inferred by cytological analyses. Thirteen of these inversions occurred in the D. mojavensis lineage: 12 are fixed and one of them is a polymorphic inversion previously described in populations from Sonora and Baja California, México. We previously investigated the breakpoints of chromosome 2 inversions fixed in D. mojavensis. Here we characterized the breakpoint regions of the 5 inversions found in chromosome 3 in order to infer the molecular mechanism that generated each inversion and its putative functional consequences. Overall, our results reveal a number of gene alterations at the inversion breakpoints with putative adaptive consequences that point to natural selection as the cause for fast chromosomal evolution in D. mojavensis.