To downregulate the immune system after systemic insult, activated B and T lymphocytes upregulate Fas, and activated T lymphocytes upregulate Fas ligand. These two interact through the Fas-activating death domain (FADD) to trigger the caspase cascade, leading to cellular apoptosis. Apoptosis mediated through the FAS death receptor is part of the extrinsic apoptotic pathway. In contrast, apoptosis initiated in the mitochondria is part of the intrinsic apoptotic pathway. Patients with ALPS and DALD have a defect in the FAS apoptotic pathway. ALPS and DALD patients develop lymphoproliferation and autoimmune disease. ALPS patients have elevated peripheral blood DNTs, a hallmark of the disease, whereas DALD patients do not. Patients with ALPS typically have elevated serum levels of IL-10 and IL-18. Boggio et al demonstrate that DALD patients do not have elevated IL-10 or IL-18 levels. They also make the novel observations that both ALPS and DALD patients have elevated IL-17A and IL-17F levels as well as elevated IL-1β levels, providing a number of potential therapeutic targets for future investigations. Adapted with permission from a professional illustration by Sue Seif.