There is a growing appreciation that patients with seizures are also affected by a number of comorbid conditions, including an increase in prevalence of depression (Kanner, 2009), sleep apnea (Chihorek et al., 2007), and sudden death (Ryvlin et al., 2006; Tomson et al., 2008). The mechanisms responsible for these associations are unclear. Herein we discuss the possibility that underlying pathology in the serotonin (5‐HT) system of patients with epilepsy lowers the threshold for seizures, while also increasing the risk of depression and sudden death. We propose that postictal dysfunction of 5‐HT neurons causes depression of breathing and arousal in some epilepsy patients, and this can lead to sudden unexpected death in epilepsy (SUDEP). We further draw parallels between SUDEP and sudden infant death syndrome (SIDS), which may share pathophysiologic mechanisms, and which have both been linked to defects in the 5‐HT system.