Introduction In the past decade, delivering personalized medicine via molecularly targeted therapies has become a major focus in the field of cancer therapeutics. Tyrosine kinases regulate angiogenesis and cell proliferation, invasion, and apoptosis. Tyrosine-kinase inhibitors (TKIs) are small-molecule inhibitors that permeate through the cell membrane and target specific portions of kinase receptors in cancer cells and/or the surrounding endothelium and vasculature. In this chapter, we review the TKIs currently used to treat cancer, including targeted agents, angiogenesis inhibitors, and Her family inhibitors (Figure 82.1). Imatinib mesylate Imatinib mesylate (STI-571; Gleevec/Glivec, Novartis Pharmaceuticals), the first TKI developed for Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia (CML), specifically targets the translocation that encodes the breakpoint cluster region–Abelson (BCR–ABL) tyrosine kinase (Figure 82.2). Imatinib also inhibits normal ABL. The BCR–ABL fusion gene is found in 90% of patients with CML and 15–30% of patients with acute lymphoblastic leukemia (ALL; 1). BCR–ABL activates multiple cytoplasmic and nuclear signal-transduction pathways, including Ras, phosphatidylinositol-3 kinase (PI3K), protein kinase B (AKT), and Jak/Stat, and up-regulates interleukin-3 and focal adhesion kinase. BCR–ABL is associated with an impaired DNA-repair response that promotes genetic abnormalities (2–10). In addition, imatinib inhibits c-Kit receptor and platelet-derived growth-factor receptor (PDGFR)-α and -β.