Interferon-alfa (IFNalpha) became the first-line agent for the treatment of chronic myeloid leukemia (CML) because it prolongs survival significantly compared to conventional chemotherapy (CHT). Responses to IFNalpha and the benefits from achieving a response are greater in low-risk than in high-risk patients. The best therapeutic results are obtained in low-risk patients who achieve a complete hematologic response (CHR) within 3 to 6 months, a major cytogenetic response (MCgR) within 1 year, and a complete cytogenetic response (CCgR) thereafter. Cytogenetic responses (CgRs) to IFNalpha are stable and durable, so that about 50% of complete responders become long-term survivors. Combining IFNalpha with other drugs, like arabinosyl cytosine (AC), and with other treatments, like autologous stem cell transplantation (autoSCT), may provide additional benefit, although this has not been proven. The biologic and molecular bases of the action of IFNalpha are still poorly understood, but are worth investigating further to determine whether it will still have a therapeutic role when used in combination with the protein tyrosine kinase inhibitors and other new agents.