Infections with avian pathogenic Escherichia coli (APEC) can be extremely detrimental to poultry health and production. Investigating host genetic variation could identify the biological mechanisms that control resistance to this pathogen and allow selection for improved resistance in experimental and commercial poultry populations. In this review, the current knowledge of how host genetics contributes to APEC resistance and future opportunities that would benefit the understanding or application of genetic resistance are discussed. Phenotypes, such as antibody responses, lesion scores, and mortality, revealed that genetic background impacts APEC resistance and interacts with other factors including the environment and challenge conditions. Experiments have used divergent selection for APEC-specific antibody levels to facilitate genetic studies, estimated heritabilities in relevant traits, detected quantitative trait loci using microsatellites, and made associations with sequence variation in the major histocompatibility complex, which collectively suggest that improving APEC resistance through selection is feasible, although genetic control is partial, complex, and highly polygenic. Additionally, functional genomics techniques have identified antimicrobial responses, toll-like receptor and cytokine signalling, and the cell cycle as central pathways in the host response to APEC challenge. Opportunities for future research are discussed, including the expansion of existing lines of research and the application of new technologies that are relevant to the study of host genetics and APEC. This review closes with prospective strategies for improvement of host genetic resistance to APEC.