Although the prognosis of children with ALL has improved markedly, approximately one-half of children continue to relapse. Clinical and biologic features of ALL have been studied at the time of diagnosis and many of these features have been shown to predict the risk of relapse, permitting tailoring of therapy based on relapse hazard. Results of studies of the Pediatric Oncology Group (POG) detailed here demonstrate that high white blood cell (WBC) count at diagnosis, very young or older age within childhood, and the presence of a mediastinal mass or central nervous system leukemia predict a poor prognosis within the context of certain therapies. However, not only age and WBC count, but immunophenotype of ALL as well, were especially predictive of prognosis in these POG studies. The information reviewed here has special importance for the planning of clinical trials for children with ALL.