Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. Clinical manifestations include noninfectious and nonmalignant lymphadenopathy, splenomegaly, and autoimmune pathology-most commonly, autoimmune cytopenias. Rarely, and in association with specific genetic mutations, patients with ALPS may go on to develop secondary lymphoid malignancies. Though ALPS is a rare disorder, it should be suspected and ruled out in children presenting with chronic and refractory multilineage cytopenias associated with nonmalignant lymphoproliferation. Revised diagnostic criteria and insights into disease biology have improved both diagnosis and treatment. Sirolimus and mycophenolate mofetil are the best-studied and most effective corticosteroid-sparing therapies for ALPS, and they should be considered first-line therapy for patients who need chronic treatment. This review highlights practical clinical considerations for diagnosis and management of ALPS.