The BCR‐ABL translocation represents the first pathognomonic genetic event described in oncology. It is now known that a reciprocal translocation results in a fusion of the breakpoint cluster region (BCR) gene on chromosome 22 and the c‐Abl gene on chromosome 9. This fusion kinase (BCR‐ABL) provides antiapoptotic and proliferative signals that confer a competitive Darwinian advantage to the malignant clone. The advent of imatinib, a BCR‐ABL tyrosine kinase inhibitor, first provided proof‐of‐principle that molecularly targeted therapy could be an effective, non‐toxic treatment for many cancers. Here, we discuss the molecular pathology of BCR‐ABL in CML as it relates to oncogenesis, therapy, and drug resistance.