Novel regulatory elements that enabled expression of pre‐existing immune genes in reproductive tissues and novel immune genes with pregnancy‐specific roles in eutherians have shaped the evolution of mammalian pregnancy by facilitating the emergence of novel mechanisms for immune regulation over its course. Trade‐offs arising from conflicting fitness effects on reproduction and host defenses have further influenced the patterns of genetic variation of these genes. These three mechanisms (novel regulatory elements, novel immune genes, and trade‐offs) played a pivotal role in refining (...) the regulation of maternal immune systems during pregnancy in eutherians, likely facilitating the establishment of prolonged direct maternal–fetal contact in eutherians without causing immunological rejection of the genetically distinct fetus. (shrink)