Sudden unexpected death in epilepsy is likely caused by a cascade of events affecting the vegetative nervous system leading to cardiorespiratory failure and death. Multiple genetic, electrophysiological, neurochemical, and pharmacological cardiac alterations have been associated with epilepsy, which can affect autonomic regulation of the heart and predispose patients to sudden unexpected death in epilepsy. These cardiac and autonomic changes are more frequently seen in patients with longstanding and medication refractory epilepsy and may be a prerequisite for sudden unexpected death in epilepsy. Cardiac changes are also observed within the immediate periictal period in patients with and without preexisting cardiac pathology and could be the tipping point in the cascade of events compromising autonomic, respiratory, and cardiac function during an epileptic convulsion. Better understanding if and how these cardiac alterations can make a particular individual with epilepsy more susceptible to sudden unexpected death in epilepsy will hopefully lead us to more effective preventative strategies.