STI571 (imatinib mesylate) is an example of the successful development of a targeted agent. Its target is the constitutively active tyrosine kinase (p210bcr–abl) in a hematologic neoplasm, chronic myelogenous leukemia (CML). The results in early clinical trials were remarkable and led to rapid approval by the Food and Drug Administration for clinical use of the STI571 in CML. This article reviews the pre-clinical and clinical development of this agent and also discusses some of the prevailing theories to explain the emerging problem of resistance. Future directions for this drug, possibly directed at other targets, are also discussed.