The evolution of mate choice for genetic benefits requires a continuous supply of genetic variation in the population to preserve the incentive to be choosy. Hamilton and Zuk's influential hypothesis (1982) proposed that co-evolution with parasites can maintain such supply of genetic variation in immune resistance genes that influence preferred traits. The major histocompatibility complex (MHC), vital for its role in the adaptive immune response, is by far the most investigated immune gene in mate choice studies (Winternitz & Abbate, 2022), and for good reason. It is one of the most polymorphic gene regions in vertebrates, and this diversity is believed to be maintained by pathogen-mediated balancing selection and sexual selection (Radwan et al., 2020). MHC-based sexual selection, including mate choice and post-mating selection, has been intensively studied, but despite more than 40 years of investigation, our understanding is limited. We still know very little about which MHC-based mechanisms may be at play, their timing during the mating process (i.e., pre-or post-copulatory) or their importance relative to genomewide-based mating preferences such as inbreeding avoidance.Indeed, most studies are limited to questions that can be asked from a particular study system, with nonmodel populations producing the most evolutionarily relevant results but suffering from small sample sizes, patchy population data and incomplete MHC genotyping.The study by Huang et al. (2021) in this issue of Molecular Ecology illustrates the complexity of identifying MHC-based sexual selection