Activated PI3-kinase-δ syndrome (APDS) is a rare primary combined immunodeficiency caused by either dominant gain-of-function mutations in the PIK3CD gene encoding the catalytic subunit p110δ of phosphoinositide 3-kinase-δ (PI3K-δ) (referred to as type 1 APDS) or dominant loss-of-function mutations in the PIK3R1 gene encoding the p85α, p55α and p50α regulatory subunits (type 2 APDS). In types 1 and 2 APDS, the PI3K-δ hyperactivity resulting from the gene mutations leads to similar clinical presentations - characterized by increased susceptibility to bacterial and viral infections, and (to a lesser extent) by auto-immune manifestations. A hallmark of this disease is the occurrence of lymphoproliferation, which may even be life-threatening and require repeated surgical treatment. A major complication of APDS is the occurrence of malignancy (especially B lymphomas), which greatly worsens the prognosis. Here, we review the different neoplastic conditions observed in patients with APDS, and discuss the uncontrolled PI3K-δ activity in B and T cells that leads to malignant transformation.