Advances in next-generation sequencing technologies have liberated our dependency on model laboratory species for answering genomic and transcriptomic level questions. These new techniques have dramatically expanded our breadth of study organisms and have allowed the analysis of species from diverse ecological environments. One such species is the cactophilic Drosophila mojavensis that inhabits the deserts of western North America. These insects feed and develop in the necrotic cacti, feeding largely on the microflora of the necrotic plant tissues. Drosophila mojavensis is composed of four geographically and ecologically separated populations. Each population (Baja California peninsula, mainland Sonoran Desert, Mojave Desert and Santa Catalina Island) utilizes the necrotic tissues of distinct cactus species. The differences in the nutritional and chemical composition of the necroses include a set of toxic compounds to which resident population must adapt. These ecological differences have facilitated many of the life history, behavior, physiological and genetic differences between the cactus host populations. Genomic resources have allowed investigators to examine the genomic and transcriptional level changes associated with the local adaptation of the four D. mojavensis populations, thereby providing further understanding of the genetic mechanism of adaptation and its role in the divergence of ecologically distinct populations.