We studied 50 patients with childhood acute lymphoblastic leukemia (ALL), including 11 with T-cell ALL and 39 with non-T-cell, non-B-cell ALL. In addition to characterizing surface-antigen expression and immunoglobulin-gene rearrangement, we determined whether the T-cell receptor beta-chain gene also undergoes somatic rearrangement. All 11 patients with T-cell ALL had rearrangements of the beta-chain gene, with no persistence of the germline configuration. In two of these patients we demonstrated rearrangements of both the T-cell receptor gene and the immunoglobulin mu-heavy-chain gene. All 39 patients with non-T-cell, non-B-cell ALL had immunoglobulin heavy-chain gene rearrangements; in addition, 10 had rearrangements of the T-cell receptor beta-chain gene, indicating heterogeneity at the level of the T-cell receptor gene in this form of the disease. The results of our analysis of T-cell receptors and immunoglobulin heavy-chain genes offer new insight into normal and abnormal lymphocyte differentiation.