Although a number of factors have contributed to the decline and extinction of Hawai‘i’s endemic terrestrial avifauna, introduced avian malaria (Plasmodium relicturn) is probably the single most important factor preventing recovery of these birds in low-elevation habitats. Continued decline in numbers, fragmentation of populations, and extinction of species that are still relatively common will likely continue without new, aggressive approaches to managing avian disease. Methods of intervention in the disease cycle such as chemotherapy and vaccine development are not feasible because of efficient immune-evasion strategies evolved by the parasite, technical difficulties associated with treating wild avian populations, and increased risk of selection for more virulent strains of the parasite. We are investigating the natural evolution of disease resistance in some low-elevation native bird populations, particularly Hawai‘i ‘Amakihi (Hemignathus virens), to perfect genetic methods for identifying individuals with a greater immunological capacity to survive malarial infection. We are focusing on genetic analyses of the major histocompatibility complex, due to its critical role in both humoral and cell-mediated immune responses. In the parasite, we are evaluating conserved ribosomal genes as well as variable genes encoding cell-surface molecules as a first step in developing a better understanding of the complex interactions between malarial parasites and the avian immune system. A goal is to provide population managers with new criteria for maintaining long-term population stability for threatened species through the development of methods for evaluating and maintaining genetic diversity in small populations at loci important in immunological responsiveness to pathogens.