Current cancer therapies improve the overall survival of cancer patients. However, cardiotoxicity is one of the most recognized complications following treatment with conventional chemotherapy, targeted drugs, and chest irradiation. Cardiotoxicity can range from subclinical myocardial injury to symptomatic heart failure. Once left ventricular dysfunction or heart failure is clinically detected, these cancer therapies need to be suspended, leading to the risk of cancer progression or recurrence. Anthracyclines and HER2-targeted drugs are notably common chemotherapeutic drugs that directly impair the myocardium. Doxorubicin, a widely used anthracycline, causes irreversible cardiotoxicity in a cumulative dose-related manner through oxidative stress, mitochondrial dysfunction, and DNA double-strand breakdown. Trastuzumab is the first monoclonal antibody to be selectively effective against HER2-overexpressing cancers. Unlike anthracycline, trastuzumab-induced cardiotoxicity is believed not to be dose-related and is typically manifested during treatment. HER2 inhibition impairs mitochondrial function and defense mechanisms against oxidative stress, leading to cardiac dysfunction. The cardiotoxicity is reversible after trastuzumab discontinuation and the rechallenge of the treatment is potentially safe. HER-2-positive breast cancer is typically treated with anthracyclines and sequentially followed by trastuzumab; however, trastuzumab may augment doxorubicin-induced cardiotoxicity. Close monitoring and periodic surveillance of left ventricular function are critical during and after cancer treatment to enable detection of cardiotoxicity. Although several drugs, including dexrazoxane and angiotensin-converting enzyme inhibitors, have been demonstrated to be beneficial in attenuating cardiotoxicity, there is still no effective prevention to reduce cardiovascular events in patients receiving either anthracyclines or trastuzumab. Novel preventive interventions involving oxidative stress, mitochondrial function, and autophagy have been reported in preclinical models, and they could potentially be clinically effective in preventing this cardiotoxicity in the future.