The biology of acute leukemia is studied and innovative approaches to its treatment explored with particular emphasis on investigation of acute lymphocytic leukemia (ALL). Biological studies are aimed at elucidating characteristics of the biology of the acute leukemic cells which will provide avenues for new therapeutic approaches. Biochemical studies have defined the crucial role of the purine pathway enzymes in lymphoid malignancies. Immunological studies have 1) confirmed the potential of in vitro monoclonal antibody immunotherapy of acute leukemia in a unique murine model; 2) examined the role of ALL cells in suppression of the immune response; and 3) evaluated the status of immunoglobulin gene rearrangement in leukemic lymphoblasts. Study of sex steroid receptors has demonstrated estrogen receptors on the leukemic cells of a subset of ALL patients, and in a murine model, has confirmed their role in leukemogenesis. Therapeutic studies in ALL have addressed 1) improvement in therapy for patients in the high risk category; 2) assessment of mechanisms of treatment failure; and 3) characterization of adverse sequelae of antileukemic therapy and design of treatment regimens which avoid them. The major ALL treatment protocol has successfully demonstrated that high-dose, protracted systemic methotrexate infusions can substitute for cranial radiation as central nervous system CNS preventive therapy for the majority of patients with ALL. Studies on the bioavailability of orally administered maintenance chemotherapy reveal that many patients do not achieve adequate drug levels in the blood, indicating a probable mechanism of treatment failure. A clinical trial of 2 foot -deoxycoformycin and Ara-A seeks to take selective advantage of the specific biochemical abnormalities uncovered in our studies of leukemic lymphoblasts. Demonstration of Leydig cell dysfunction in patients treated for testicular relapse confirms the need for hormonal replacement therapy. Studies on late effects have demonstrated CT brain scan, neuroendocrine, and psychometric test abnormalities in long-term survivors, stressing the need for alternative methods of CNS preventive therapy.