In 2024, there will likely be 20 million new cancer cases (approximately 10 million cancer deaths) worldwide. While anti-cancer drugs like doxorubicin (DOX) are beneficial, they often induce off-target effects such as skeletal muscle fatigue and weakness. These myopathies affect up to 80% of cancer patients, persisting long after treatment cessation. Unfortunately, effective treatments are lacking due to a limited understanding of the underlying molecular mechanisms affected by DOX. Most past studies focused on DOX-driven oxidative stress & mitochondrial dysfunction in muscle; still, there is growing evidence that the chemotherapy drug side effects in muscle are multifactorial. Indeed, preliminary results reveal that DOX directly affects Ca homeostasis, increases mitochondrial ATP & ROS production, reduces muscle strength & decreases fatigue resistance. Further, we found that the small molecule MP-001, an inhibitor of Ca leak, mitigates these DOX-driven abnormalities. This discovery presents a promising therapeutic intervention to minimize the debilitating effects of this chemotherapy agent on skeletal muscle.