In anticancer drug development, there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can influence decision making during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. In this comprehensive review, we will analyze potential effects on QTc prolongations of targeted agents approved by regulatory agencies and under investigation. A thoughtful risk management plan was generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development program essential for oncology agents with cardiac safety concerns.