The field of human genetics of infectious diseases defines the genes and alleles rendering individuals (clinical genetics) and populations (epidemiological genetics) vulnerable to infection, and studies those selected by previous infections (evolutionary genetics). These disciplines—clinical, epidemiological and evolutionary genetics—delineate the redundant and nonredundant functions of host defense genes for past and present survival in natura—in natural ecosystems governed by natural selection. These disciplines, in other words, assess the ecologically relevant and evolutionarily selected roles of human genes and alleles in protective immunity to diverse and evolving microorganisms. The genetic dissection of human immunity to infection in natura provides unique immunological insight, making it an indispensable complement to experimental immunology in vitro and in vivo in plants and animals.