Mutations in human genes involved in immunity are increasingly recognised. Most are associated with conventional primary immunodeficiencies, which confer Mendelian predisposition to multiple infectious diseases. Recently, there has been much study of monogenic traits that do not confer such a broad vulnerability. Defects in several genes confer predisposition to infection with specific bacteria and viruses in otherwise healthy individuals. Mutations in other genes even confer resistance to specific pathogens, with no detectable decrease in fitness. These ‘experiments of nature’ reveal surprising specific interactions between certain human genes and microbial pathogens.