Autoimmune hemolytic anemia (AIHA) is an autoimmune disorder in which autoantibodies are directed against an individual's own red blood cells (RBCs), leading to enhanced clearance through Fc receptor (FcR)-mediated phagocytosis. Although there is a large literature relating to clinical aspects of AIHA, relatively little work addresses how IgG autoantibodies are actually produced against RBC autoantigens. This review will first discuss the current understanding of autoimmunity in general and then focus on the knowledge of the immunopathogenic mechanisms responsible for autoantibody production in AIHA. Both human and animal studies will be discussed. Understanding theses mechanism is vital for developing antigen-specific immunotherapies to treat the disease.