Acute lymphoblastic leukemia (ALL) is the most common cancer in children and is among the most curable of the pediatric malignancies. Many clinical, biological, genetic, and molecular features have been identified as having prognostic significance in the outcome of patients with ALL. The standard features are age and WBC at diagnosis, with infants (less than one year), adolescents (greater than nine years), and children with WBC above 50,000/microl being at higher risk. Certain chromosomal abnormalities are also strong predictors; in particular, the Philadelphia chromosome and MLL gene rearrangements (especially in infants) are adverse features, while TEL-AML1 is favorable. It is important to note, however, that even the most important known predictors explain only a small proportion of the variability in outcome. These features are currently used to tailor the intensity of treatment so that the toxicity of treatment can be minimized and cure rates can continue to improve. This article reviews time-honored prognostic features, recent advances, and future directions in this field.