Recent progress on the studies of cold agglutinin disease and paroxysmal cold hemoglobinuria is reviewed. In both types of autoimmune hemolytic anemia, auto-antibodies are directed specifically to the antigenic epitopes which have physiological significance as differentiation antigens. They are the metabolic precursors for the synthesis of strong allo-antigens such as ABO(H). Although both antigen epitopes, i.e., differentiation and allo-antigen epitopes, are present on the red blood cells, the autoimmune reaction is directed specifically to the differentiation antigen epitopes, and not directed to the strong allo-antigenic epitopes. Most of auto-antigens also serve as receptors for some viruses, bacteria and drugs. Recent analysis on the sequence of auto-antibodies indicated that most of the auto-antibodies in cold agglutinin disease are encoded by the VH-4-21 gene of VH4 family, indicating the auto-antibodies are produced by dysregulation of very limited B cell clones. This implies that immune system is prone to be disturbed with self differentiation antigens rather than strong self allo-antigens, and that the dysfunction of auto-reactive B cell clones could be triggered by infection of some viruses and bacteria, or by certain medication.