Host-pathogen interactions shape the evolution of host immune defense. Genetic variation in genes of the immune system influences resistance to infection, but host immune defenses can additionally be influenced by environmental and physiological factors, including the presence of symbiotic microbes. In this thesis I examine both non-genetic and genetic factors involved in host-pathogen interactions. In the first chapter I ask whether the antibacterial immune response of D. melanogaster is influenced by the endosymbiotic bacterium Wolbachia pipientis, and in the second chapter I investigate whether immune system genes of the malaria mosquito Anopheles coluzzii show signatures of pathogen-driven coevolution. The endosymbiotic bacterium Wolbachia pipientis confers D. melanogaster and other insects with resistance to infection by RNA viruses. I investigated whether Wolbachia infection plays a role in protecting D. melanogaster against secondary bacterial infection, and in particular against pathogenic intracellular bacteria. I found no evidence that Wolbachia alters resistance to any of the bacterial pathogens tested, irrespective of how they colonize the host. The ability to resist and/or survive infection is a critical determinant of host fitness, so natural selection is predicted to drive the evolution of resistance mechanisms in response to novel or coevolving pathogens. I used molecular population genetic analyses to investigate how natural selection operates on the immune system of Anopheles coluzzii. I found evidence of rapid adaptive evolution in STAT-B, and long-term balancing selection in CTLMA2. In contrast to these Anopheles-specific immune genes, we found that genes encoding the Imd immune pathway, which are orthologously conserved across insects, exhibit patterns of genetic variation consistent with relaxed purifying selection. These results indicate that adaptive coevolution between A. coluzzii and its pathogens is more likely to involve novel or lineage-specific molecular mechanisms than the canonical humoral immune pathways.