In clinical trials conducted at St Jude Children's Research Hospital, etoposide has proved to be an effective agent for the treatment of advanced childhood leukemias. When combined with 5-azacytidine, it induced complete remissions in about one-half of patients with refractory ANLL. The same induction rate was achieved in patients with refractory ALL receiving etoposide with prednisone and vincristine. Results of continuing studies should help to identify the optimal schedules and dosages for this epipodophyllotoxin. The acceptance of new antileukemic drugs into clinical practice has slowed over the past decade. Etoposide is but one of several new agents that hold promise of moving leukemia therapy beyond its present barriers.