The differential diagnosis of anemia must consider immune hemolytic anemias as a frequent cause. Whereas detection of anti-red blood cell (RBC) alloantibodies frequently induced by immunogenic stimuli (transfusion, pregnancy) is performed by routine serology, diagnosing autoimmune hemolytic anemias or drug-induced hemolytic anemias remains a challenge, usually requiring close collaboration of a number of disciplines. Positive direct antiglobulin test (Coombs’ test) represents a central criterion in diagnosing immune hemolytic anemias, leading to further detailed analyses. The most-severe type of immune-mediated hemolysis is acute intravascular hemolysis after ABO incompatible RBC transfusion. This review highlights underlying biochemical aspects, immunohematological diagnostics, and the clinical relevance of RBC allo- and autoantibodies, including paroxysmal nocturnal hemoglobinemia and drug-induced hemolysis. Finally, current and partly experimental therapeutic strategies of immune hemolytic anemias are summarized.