Conflicting results have been reported in recent years concerning the incidence and prognostic relevance of acute mixed-lineage leukemias (AMLL). Among the high number of possible hybrid antigen combinations, it is important to discriminate those occurring with sufficient frequency to be of general clinical significance. In this review an approach to a classification based upon the hierarchical import of developmental antigens seen during hemopoietic differentiation is suggested. As far as the clinical relevance of AMLL is concerned, some hybrid patterns have been found to be associated with distinct characteristics in terms of clinical features at the time of presentation and poor response to treatment. For these particular types of leukemia, the time has probably arrived to design more specific therapeutic regimens.