Understanding primary immunodeficiencies has elucidated many aspects of human immunity and susceptibility to infections. Recently, defects have been identified that result in deficiencies of terminally differentiated subsets of lymphocytes including deficiencies of memory B cells, NKT cells and T_h17 T cells. Together with defects specific to T_h1 responses, these disorders revealed that dedicated pathogen-specific mechanisms exist for prevalent human pathogens, and that some host defence strategies are remarkably specific. Deficiency of T_h17 cells confirms that this subset of effector T cells is important for defence at epithelial surfaces. The clinical phenotype includes devastating complications from infection with Staphylococcus aureus. Since the microbial load at human epithelial surfaces is substantial and enormously diverse, this specificity could hold clues that are important for understanding first the complex symbiosis with mucosal commensals and second for understanding the consequences of manipulating these populations in inflammatory diseases.