Two new studies report heterozygous gain-of-function mutations in PIK3CD, which encodes the catalytic subunit of phosphatidylinositol 3-kinase δ (PI3K δ), as the cause of a primary immunodeficiency syndrome. Sergey Nejentsev and colleagues (Science doi:10.1126/science.1243292, 17 October 2013) found a recurrent PIK3CD mutation leading to a p.Glu1021Lys alteration in seven unrelated families with a history of respiratory infections and progressive airway damage. In an independent study, Gulbu Uzel and colleagues (Nat. Immunol. doi:10.1038/ni.2771, 28 October 2013) identified three distinct PIK3CD mutations, resulting in p.Asn334Lys, p.Glu525Lys and p.Glu1021Lys alterations, in seven unrelated families presenting with sinopulmonary infections, chronic viremia and lymphoproliferation. Both groups showed that the mutations resulted in increased PI3K activity, increased phosphorylation of AKT and altered T and B cell function. In particular, Uzel and colleagues found that the mutations were associated with a deficiency of naive T cells and an excess of senescent effector T cells. Both studies also present preliminary data suggesting that individuals harboring these activating mutations in PIK3CD could benefit from treatment with selective PI3Kδ inhibitors or with mTOR inhibitors such as rapamycin.