Antibodies (ABs) that target autoantigens were more abundant in the blood of humans and animals suffering from certain autoimmune and viral diseases than in the blood of healthy donors. The emergence of ABs with diverse types of catalytic activity is among the earliest manifestations of certain autoimmune diseases. The putative mechanisms that underlie the accumulation of autoantibodies and abzymes in different autoimmune diseases are addressed in the present review. The extraordinary diversity of abzymes with various types of catalytic activity is discussed.