The identification of immunophenotypes expressed on leukemic cells but rare or absent during normal hematopoiesis allows close monitoring of residual leukemia after treatment. Phenotypes that afford a detection level of 1 leukemic cell among 10,000 normal bone marrow cells have been identified in 90% of cases of T-lineage acute lymphoblastic leukemia (T-ALL), 25% of B lineage ALL and 40% of acute myeloid leukemia (AML). Residual disease detected with immunologic techniques in patients with acute leukemia during continuation therapy or off treatment usually anticipates overt relapse. While these data indicate the reliability of these techniques, further studies with homogeneously treated cohorts of patients, currently underway, are needed to precisely define the clinical significance of detecting occult leukemia at different points during treatment. The proportion of patients that can be studied with immunologic methods may increase through the definition of new leukemia-associated phenotypes using existing antibodies. In addition, new useful phenotypes may be identified through a) the development of novel techniques that allow cell permeabilization with preservation of surface membrane molecules and light-scattering properties; b) the generation of new antibodies that recognize leukemia-associated antigens.