Protein tyrosine kinases (PTKs) are critical in regulating cell growth and differentiation and are deeply involved in several cancers. PTK-inhibitors are mainly ATP-site directed and are finding use in the treatment of several cancers, and more than 30 such agents are now in phase I-III clinical trials. The present review focuses mainly on the development of PTK inhibitors in clinical trials, with special emphasis on imatinib mesylate, a rationally designed, potent oral anticancer agent and selective inhibitor for Abl tyrosine kinase, including Bcr-Abl, C-kit and platelet-derived growth factor-receptor tyrosine kinases, which has been implicated in several malignancies, including chronic myeloid leukemia and gastrointestinal stromal tumour.