Warm autoimmune hemolytic anemia (wAIHA) is caused by increased erythrocyte destruction by IgG autoantibodies, with or without complement activation. Antibody-dependent cell-mediated cytotoxicity by macrophages/activated lymphocytes occurs in the lymphoid organs and spleen (extravascular hemolysis). The ability of the bone marrow to compensate determines clinical severity. The different pathogenic mechanisms, their complex interplay, and changes over time may explain wAIHA's great clinical heterogeneity and unpredictable course. The disease may be primary, drug-induced, or associated with lymphoproliferative neoplasms, autoimmune and infectious diseases, immunodeficiencies, solid tumors, or transplants. Therapeutic interventions include steroids, splenectomy, immunosuppressants, and rituximab; the latter is increasingly used in steroid refractory cases based on evidence from the literature and a few prospective trials. We present five patient case studies highlighting important issues: 1) the diagnosis and proper use of steroid therapy; 2) the concerns about the choice between rituximab and splenectomy in second-line treatment; 3) the need of periodical re-evaluation of the disease to assess the possible evolution of relapsed/refractory cases in myelodysplastic and bone marrow failure syndromes; and 4) the difficulties in managing cases of severe/acute disease which are at high risk of relapse. Incorporating novel targeted therapies into clinical practice will be an exciting challenge in the future.