The major histocompatibility complex (MHC) is a paradigm for understanding how selection maintains genetic diversity in natural populations. This review highlights the contributions of studies on MHC in non-model species to our understanding of how selection affects MHC diversity, emphasizing the influence of ecological and ethological processes on the tempo and mode of MHC evolution, and how MHC variability affects individual fitness, population dynamics, and viability. The review focuses on three main areas: the types of information used to detect selection on MHC genes, the relative contributions of parasite-mediated and sexual selection to MHC diversity maintenance, and potential future research directions to resolve unanswered questions about MHC evolution. The MHC plays a central role in vertebrate immune systems, encoding key receptor molecules that recognize and present foreign peptides to immune cells. Despite extensive research, the evolutionary, ecological, and ethological processes that generate and maintain MHC diversity remain poorly understood. The review discusses the structure and function of the MHC, methods for detecting selection in contemporary and historical populations, and the role of parasite-mediated and sexual selection in MHC evolution. It also highlights the importance of studying non-model species to better understand the ecological significance of MHC diversity and the mechanisms underlying MHC evolution.The major histocompatibility complex (MHC) is a paradigm for understanding how selection maintains genetic diversity in natural populations. This review highlights the contributions of studies on MHC in non-model species to our understanding of how selection affects MHC diversity, emphasizing the influence of ecological and ethological processes on the tempo and mode of MHC evolution, and how MHC variability affects individual fitness, population dynamics, and viability. The review focuses on three main areas: the types of information used to detect selection on MHC genes, the relative contributions of parasite-mediated and sexual selection to MHC diversity maintenance, and potential future research directions to resolve unanswered questions about MHC evolution. The MHC plays a central role in vertebrate immune systems, encoding key receptor molecules that recognize and present foreign peptides to immune cells. Despite extensive research, the evolutionary, ecological, and ethological processes that generate and maintain MHC diversity remain poorly understood. The review discusses the structure and function of the MHC, methods for detecting selection in contemporary and historical populations, and the role of parasite-mediated and sexual selection in MHC evolution. It also highlights the importance of studying non-model species to better understand the ecological significance of MHC diversity and the mechanisms underlying MHC evolution.