The chromosomal translocation t(9;22)(q34;q11), known as the Philadelphia (Ph) chromosome, results in the BCR-ABL gene fusion which gives rise to Chronic Myeloid Leukemia (CML), a slowly progressing hematopoietic cancer that begins in the bone marrow of the patient. Making up about 15 % of all new leukemia cases, CML remains a critical focus of cancer research and treatment due to its distinctive genetic hallmark, the BCR-ABL fusion gene. The BCR-ABL fusion protein is a constitutively active tyrosine kinase which signals to multiple pathways including the Ras/MAPK, PI3K/AKT, JAK/STAT and NF-kappaB pathways which promote uncontrolled cell proliferation and survival. While multiple tyrosine kinase inhibitors (TKIs) are used to specifically target the fusion in the treatment of CML, new therapies are becoming available to overcome the resistance that occurs during TKI treatments of the disease. The discovery of the Philadelphia chromosome and the subsequent elucidation of the BCR-ABL fusion protein have since become a paradigm for understanding the genetic basis of cancer and developing precision medicine approaches. This review highlights the etiology and historical discovery of the BCR-ABL fusion, recent advances in understanding its regulatory mechanisms, and emerging strategies for its therapeutic targeting.