Imatinib mesylate (Gleevec), a small-molecule inhibitor of the Bcr-Abl fusion protein, is associated with cardiotoxicity. This study reports severe left ventricular dysfunction and heart failure in ten patients treated with imatinib, along with similar effects in imatinib-treated mice. Transmission electron microscopy revealed mitochondrial abnormalities and accumulation of membrane whorls in both humans and mice, suggesting a toxic myopathy. In cultured cardiomyocytes, imatinib activated the endoplasmic reticulum (ER) stress response, collapsed the mitochondrial membrane potential, released cytochrome c, reduced ATP levels, and caused cell death. Retroviral gene transfer of an imatinib-resistant c-Abl mutant, or inhibition of ER stress or JNK pathways, rescued cardiomyocytes from imatinib-induced death. The study shows that imatinib-induced cardiotoxicity is linked to the inhibition of c-Abl, leading to mitochondrial dysfunction and cell death. ER stress and JNK activation were found to be key pathways in this process. Imatinib caused significant mitochondrial swelling, cytochrome c release, and necrotic cell death in cultured cardiomyocytes. The ER stress response, activated by imatinib, led to JNK activation, which contributed to mitochondrial dysfunction and cell death. Inhibition of JNK activity protected cardiomyocytes from imatinib-induced death. The study concludes that imatinib is cardiotoxic, leading to severe left ventricular dysfunction and heart failure in humans. The findings highlight the importance of monitoring patients on imatinib for signs of cardiac dysfunction and suggest that agents targeting Abl and other nonreceptor tyrosine kinases may also be cardiotoxic. The study underscores the need for prospective assessment of left ventricular function in clinical trials of new agents.Imatinib mesylate (Gleevec), a small-molecule inhibitor of the Bcr-Abl fusion protein, is associated with cardiotoxicity. This study reports severe left ventricular dysfunction and heart failure in ten patients treated with imatinib, along with similar effects in imatinib-treated mice. Transmission electron microscopy revealed mitochondrial abnormalities and accumulation of membrane whorls in both humans and mice, suggesting a toxic myopathy. In cultured cardiomyocytes, imatinib activated the endoplasmic reticulum (ER) stress response, collapsed the mitochondrial membrane potential, released cytochrome c, reduced ATP levels, and caused cell death. Retroviral gene transfer of an imatinib-resistant c-Abl mutant, or inhibition of ER stress or JNK pathways, rescued cardiomyocytes from imatinib-induced death. The study shows that imatinib-induced cardiotoxicity is linked to the inhibition of c-Abl, leading to mitochondrial dysfunction and cell death. ER stress and JNK activation were found to be key pathways in this process. Imatinib caused significant mitochondrial swelling, cytochrome c release, and necrotic cell death in cultured cardiomyocytes. The ER stress response, activated by imatinib, led to JNK activation, which contributed to mitochondrial dysfunction and cell death. Inhibition of JNK activity protected cardiomyocytes from imatinib-induced death. The study concludes that imatinib is cardiotoxic, leading to severe left ventricular dysfunction and heart failure in humans. The findings highlight the importance of monitoring patients on imatinib for signs of cardiac dysfunction and suggest that agents targeting Abl and other nonreceptor tyrosine kinases may also be cardiotoxic. The study underscores the need for prospective assessment of left ventricular function in clinical trials of new agents.