Studies in humans suggest that reproductive failure may be influenced by immunological factors or by genes encoding immunological factors and regulatory mechanisms controlling immunological expression. Using molecular methods, immunological factors can be clearly studied in an immunogenetic context. One example, the major histocompatibility complex (MHC), known as the human leukocyte antigens (HLA) in humans and MHC in other mammals, affects many different stages of reproduction. Studies in some outbred, and in closely related, human populations indicate that HLA, or HLA-linked, genes and HLA regulatory factors affect gamete development, embryo cleavage, blastocyst and trophoblast formation, implantation, fetal development and survival. Studies in non-human mammals indicate that MHC, or MHC-linked, genes such as the grc complex, Ped/Qa-2, t haplotypes and MHC regulatory factors, have similar reproductive effects. Human reproductive failure may also be a consequence of disruption of interacting factors, including interactions between HLA antigens, cytokines and natural killer (NK) cells. In this review, we highlight the importance of immunogenetic and interacting factors in human reproductive failure. We argue that studies in closely related human populations and animal models may contribute to a better understanding of the ways in which immunogenetic and interacting factors are involved in human reproduction.