<b><i>Importance:</i></b> Cardiotoxicity is an important limiting factor in the use of antineoplastic agents. The risk of arrhythmia and the electrophysiological effects of these agents are poorly characterized though increasing evidence suggests a high prevalence of complications. <b><i>Observations:</i></b> Patients with substantial cardiovascular risk factors are often excluded from clinical trials, while the aging population of patients actually receiving therapies may have an underlying arrhythmogenic substrate due to comorbidities. Risk stratification of patients before the selection of a therapeutic regimen is essential. Given the regular use of combination therapies, the potential for arrhythmia of each agent must be fully understood. Despite limited data and understanding in clinical practice, decisions on whether to initiate specific therapies in high-risk patients and how to manage the associated complications are made regularly. <b><i>Conclusions and Relevance:</i></b> This review describes the observed arrhythmias and proposed mechanisms for several major classes of antineoplastic agents. It also provides recommendations for risk stratification, monitoring, prophylaxis, and therapy, emphasizing the need for a collaborative relationship between oncologists and cardiologists and areas for future research.