The insula is known to play a central role in the regulation of autonomic function, although the precise nature and localization of such functions have not been conclusively identified. Autonomic and particularly cardiac disturbances are strongly implicated in sudden unexpected death in epilepsy (SUDEP). Herein, we discuss the contribution of the insula to seizure-related cardiac dysfunction and SUDEP. We also present two illustrative cases of intractable epilepsy patients with structural damage to the insula who succumbed to SUDEP. Both had progressive changes in heart rate variability (HRV), a standard measure of cardiac autonomic function, which noninvasively reflects sympathetic and parasympathetic balance using EKG recordings. In addition, further evidence of insular resection leading to autonomic changes is suggested in patients with intractable epilepsy and radiological evidence of insular damage after epilepsy surgery. The presence of intrinsic insular lesions or acquired insular damage in patients with refractory epilepsy may predispose to cardiac dysfunction and contribute to SUDEP pathomechanisms; however, a definitive association to SUDEP is still undetermined.