The Dobzhasnky-Muller model predicts that as species diverge over time they will accumulate genetic differences, which may be incompatible with each other when combined into the same genetic background. Despite the central importance of this process to diversification, identification of genes causing hybrid dysfunction has been primarily limited to model species. Anopheles gambiae, the principal mosquito vector of malaria in Africa, belongs to a complex of at least nine isomorphic species. In accordance with Haldane’s rule, reciprocal crosses between An. gambiae and its sister species Anopheles merus produces completely sterile males, but fully fertile females. When we backcrossed F1 hybrid females to their maternal parental males, the resulting male progeny displayed a range of phenotypes from completely sterile to completely fertile. This phenotypic range provides us with the foundation for quantitative trait locus (QTL) mapping. We performed reciprocal backcrosses, phenotyped ~2500 males from those backcrosses, and genotyped each male using a total of ~12,000 markers across the genome using a reduced representation sequencing approach. Our uniquely large quantitative genomics data set, when combined with testes-specific expression analysis, will allow us to identify a small number of hybrid-sterility candidate genes. Our current findings have shown us an intriguing result that points to a disruption sex chromosome inactivation during spermatogenesis that seems to be the cause sterility in only one of our reciprocal crosses. Not only will identification of hybrid-sterility genes provide insights into how and why postzygotic reproductive isolation barriers evolve, but they could also be important in the development of advanced sterile-insect control strategies aimed at reducing the role of the Anopheles gambiae complex in the African malaria transmission cycle.