The development of effective therapy for children with acute lymphoblastic leukemia is one of the great successes of clinical hematology andoncology. Fifty years ago, childhood acute lymphoblastic leukemia was universally fatal, but current long-term event-free survival rates are nearly 80%. Despite this improved outcome, there are still many challenges facing investigators today. In some recent clinical trials, the outcome of "high-risk" patients has approached that of "lower risk" patients, suggesting that currently applied clinical factors, such as age and presenting leukocyte count, no longer identify the 20% of newly diagnosed patients who ultimately will relapse. Additionally, therapy remains nonspecific, toxic, and sometimes lethal. As more children with acute lymphoblastic leukemia survive into adolescence and adulthood, there is a need to address the late sequelae of current therapy and to develop more leukemia-specific treatments. Promising avenues of research, which may identify biologically distinctive subsets of acute lymphoblastic leukemia and potential targets for novel therapies, include studies of minimal residual disease, lymphoblast genetics (including genetic profiling studies), and host-related pharmacogenomics.