Acute leukemia comprises a large group of different diseases that can be identified by morphology in combination with immunological markers. Such studies suggest that phenotypic heterogeneity may be expressed in individual leukemia cell populations. This was verified in the murine AKR leukemia that was found to be composed of four antigenically different subtypes of leukemia cells, and it was shown that this feature has a severe negative impact on the use of leukemia cell specific monoclonal antibodies (Mabs) as therapeutical reagents. Twenty-four human T-lymphoblastic leukemias were analyzed with Mabs against HLA class I, HLA class II, and T-lymphocyte differentiation antigens, and 21 were found to be intratumoral heterogeneous with respect to these antigens. Mabs with high specificity were generated against AML cells and subsequently used to analyze more than 50 AML samples from different patients. The reactivity pattern of the Mabs differed significantly among the various AML samples. Further, a pronounced intratumoral antigenic heterogeneity (IAH) was found in most AML samples with regard to reactivity of the Mabs against AML and expression of major histocompatibility antigens. The negative impact of IAH on the use of Mabs in clinical oncology is described. It is argued that IAH exemplifies the phenotypic diversity of malignant neoplasms which is also suggested to be a basic and necessary feature of malignant cell populations. Mabs against subsets of malignant cell populations may have a profound effect on cancerous cell populations, and it is therefore of crucial importance that such subsets are identified and characterized. It is conceivable that this may result in generation of Mabs with potentially high value in cancer diagnosis and therapy, particularly in combination with drugs that induce differentiation in the malignant cell mass.