Phosphodiesterase-5 (PDE5) inhibitors are drugs which improve the bioavailability of cyclic guanosine monophosphate (cGMP) by inhibiting its degradation by the PDE5 enzyme. Sildenafil, tadalafil and vardanefil are PDE5 inhibitors widely used for erectile dysfunction. In recent years, the clinical application of PDE5 inhibitors have expanded beyond their usage as erectile dysfunction drugs. Currently sildenafil and tadalafil are approved for the treatment of pulmonary hypertension. Mounting scientific evidence indicates beneficial use of PDE5 inhibitors in a plethora of diseases including ischemia/reperfusion injury, myocardial infarction, cardiac hypertrophy, cardiomyopathy, heart failure, benign prostatic hyperplasia, stroke and neurodegenerative diseases. We have demonstrated that PDE5 inhibitors, such as sildenafil and tadalafil, offer significant cardioprotection against ischemia-reperfusion injury, myocardial infarction, diabetic cardiomyopathy, metabolic syndrome and doxorubicin (DOX)-induced cardiomyopathy. Chemotherapy-induced cardiotoxicity is a significant concern in cancer treatment, often limiting the use of effective chemotherapeutic agents such as anthracycline antibiotics which are one of the most effective classes of chemotherapeutic agents. An anthracycline analogue, DOX is a widely used anticancer drug; however, its clinical use is limited owing to its cardiotoxicity. In this chapter, we review the critical role of long acting PDE5 inhibitor, tadalafil, in attenuating cardiotoxicity caused by chemotherapeutic agents. In particular, we will explore the key mechanisms underlying DOX-induced cardiomyopathy including oxidative stress, cardiomyocyte apoptosis and mitochondrial damage in the myocardium which ultimately contribute to heart failure. Additionally, we will highlight potential signaling pathways such as cGMP-PKG pathway and antioxidant mechanisms through which tadalafil may exert protective effects against DOX-induced cardiomyopathy and cardiotoxicity by other chemotherapeutic agents. The use of PDE5 inhibitors like tadalafil as a cardioprotective agent implicates a promising avenue for improving the cardiovascular outcomes of cancer patients undergoing chemotherapy. Future clinical trials will be essential for clarifying the role of tadalafil in cardioprotective strategies for cancer patients and for establishing its long-term safety and efficacy in this population.