Cardiotoxicity, defined as toxicity that affects the heart, is one of the most common adverse drug effects. Numerous drugs have been shown to have the potential to induce lethal arrhythmias by impacting cardiac electrophysiology, for which current preclinical testing is largely focused on the detection of such interactions. However, a substantial number of drugs can also affect cardiac function beyond electrophysiology. In this much broader sense of cardiotoxicity, this review discusses the key drug-protein interactions known to be involved in cardiotoxic drug response, expanding from adverse drug effects in electrophysiology to contractility, mitochondrial function and cellular signalling. We cover adverse effects and cardiotoxic mechanisms of anti-cancer, central nervous, genitourinary, gastrointestinal, anti-histamines, anti-inflammatory, and anti-infective agents, demonstrating they have common modes of action on cardiac function and on adverse cardiac events.