Current evidence suggests that multiple neural mechanisms contribute to the fatal lethal event in SIDS. The processes may develop from a range of otherwise seemingly-innocuous circumstances, such as unintended external airway obstruction or accidental extreme flexion of the head of an already-compromised structure of the infant upper airway. The fatal event may occur in a sleep state which can suppress muscle tone essential to restore airway patency or exert muscle action to overcome a profound loss of blood pressure. Neural processes that could overcome those transient events with reflexive compensation appear to be impaired in SIDS infants. The evidence ranges from subtle physiological signs that appear very early in life, to autopsy findings of altered neurotransmitter, including serotonergic, systems that have extensive roles in breathing, cardiovascular regulation, and thermal control. Determination of the fundamental basis of SIDS is critical to provide biologic plausibility to SIDS risk reduction messages and to develop specific prevention strategies.