Primary immunodeficiency disorders (PIDs) continue to illuminate mechanisms of human immunity and hypersensitivity. New discoveries in common variable immunodeficiency, the most enigmatic of PID syndromes, reveal molecular pathways of importance in human antibody production. FOXP3 mutations demonstrate the essential role that T-regulatory cells play in controlling autoantibody formation and disease. Interleukin-1 receptor-associated kinase 4 deficiency emphasizes the key role that innate immunity plays in the defense of bacterial disease occurring early in life. With respect to therapy, subcutaneous immunoglobulin treatment may indeed be a better treatment than intravenous immunoglobulin for many patients with antibody deficiency. Finally, PIDs remain in the vanguard for the treatment of inherited disorders by gene therapy. Gene therapy has cured patients with chronic granulomatous disease and severe combined immunodeficiency, but not without morbidity and mortality. Into the 21st century, PIDs continue to instruct us in human health and disease.