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Protein kinases are critical regulators of cell signaling and represent one of the most successful classes of drug targets in oncology. Among them, cytoplasmic tyrosine kinases (CTKs) play a pivotal role in controlling cell growth, survival, and differentiation. This review provides a comprehensive overview of CTKs as therapeutic targets, with a particular focus on the c-Abl kinase and its oncogenic counterpart, Bcr-Abl, in Chronic Myeloid Leukemia (CML). A significant portion of the review is dedicated to the development and clinical evolution of Bcr-Abl inhibitors, from first-generation ATP-competitive drugs like imatinib to second- and third-generation agents designed to overcome resistance. Finally, we discuss the clinical landscape of kinase inhibitors and future perspectives, positioning the Bcr-Abl story as a paradigm for targeted cancer therapy.