A recent surge in newly described primary immunodeficiencies (PIDs) has highlighted new physiological and pathophysiological pathways that affect the immune system. Furthermore, the study of individuals with PIDs has substantially improved our understanding of basic cellular and signalling pathways in host defence and immune regulation. Single-gene defects can lead to disease manifestations that range from extremely narrow infectious phenotypes to remarkably broad multisystem effects. Hypomorphic or hypermorphic gene mutations often occur in human diseases; when coupled with the fact that humans are exposed to naturally encountered antigens and pathogens, this helps to make the case that the study of immunological diseases in humans should be at the forefront of basic immunological research.