For patients with newly diagnosed CML, the life expectancy is much better than it was 5 years ago. However, with improvements in both transplant and nontransplant therapy comes controversy over optimal first-line therapy. We argue that an evidence-based analysis that weighs the likelihoods of surviving transplantation and responding to interferon should help guide selection of initial therapy. Such a strategy would aggressively triage appropriate patients to curative therapy while advising those who are unlikely to do well with transplantation to elect less toxic therapy, which still confers a survival benefit. We realize that many other factors beside the ones mentioned here affect a clinician's recommendation for initial therapy and a patient's ultimate choice. Many extenuating circumstances, coexisting medical conditions, and personal values need to be a part of the ultimate decision. However, we hope that this guideline summarizes the current evidence and offers a rational approach to help guide newly diagnosed patients.