Allogeneic BMT and IFN-A-based therapy have undoubtedly changed the natural history of CML. Despite these advances, many patients still die from their disease. Most patients do not qualify for an allogeneic BMT either because of age or lack of an appropriate donor, and only a fraction of patients achieve a complete cytogenetic remission with IFN-A-based therapy. The timing of BMT and treatment sequences of IFN-A and BMT have been discussed. Prior treatment with IFN-A does not seem to affect transplant outcome; however, delaying transplantation has been reported to impact adversely on transplant results. Until controlled trials are performed, the issue of optimal timing of allogeneic BMT will remain controversial. The use of alternative donors may extend the option of allogeneic BMT to younger patients; however, for older patients this therapeutic modality still has an unacceptably high incidence of morbidity and mortality with current BMT regimens and other alternative treatments are needed. Investigational strategies searching for ways of improving the proportion of patients achieving complete cytogenetic remissions with IFN-A therapy need to be actively explored. These include new agents (eg, HHT) or new modalities such as intensive chemotherapy with autologous stem cell transplantation with in vitro purging. Investigators in the field must decide whether to continue randomized trials of IFN-A versus conventional chemotherapy, or to explore strategies that may enhance the effect of IFN-A-based therapy. Only when the durable cytogenetic response rates with IFN-A combinations increase to 40% or 50% will it be of value to proceed to phase III trials. Further understanding in the basic biology of CML and the effect of IFN-A in this disease will also provide clues to improving therapy with the goal of obtaining long-term disease control and cures in the majority of patients with the least burden of therapy.