Primary immunodeficiencies are typically seen as rare monogenic conditions associated with detectable immunological abnormalities, resulting in a broad susceptibility to multiple and recurrent infections caused by weakly pathogenic and more virulent microorganisms. By opposition to these conventional primary immunodeficiencies, we investigate children with novel primary immunodeficiencies, i.e. Mendelian conditions manifesting in otherwise healthy patients as a narrow susceptibility to infections, recurrent or otherwise, caused by weakly pathogenic or by more virulent microbes. Conventional primary immunodeficiencies are suspected on the basis of a rare, striking, clinical phenotype and are defined on the basis of an overt immunological phenotype, often leading to identification of the disease-causing gene. Novel primary immunodeficiencies are defined on the basis of a more common, less marked clinical infectious phenotype, which remains isolated until molecular cloning of the causal gene reveals a hitherto undetected immunological phenotype. Similar concepts may be applied to primary immunodeficiencies presenting other clinical features, such as allergy and auto-immunity. Novel primary immunodeficiencies thus expand the clinical boundaries of this group of inherited disorders considerably, suggesting that Mendelian primary immunodeficiencies are more common in the general population than previously thought, and may affect children with a single infectious, allergic, or autoimmune disease.