One of the leading hypotheses in SIDS research is that SIDS is due to a subtle defect in brainstem neural circuits which control respiration and/or cardiac stability during sleep. We review the rationale for the brainstem hypothesis and possible mechanisms of sleep-related sudden death. We also summarize the neuropathological studies in SIDS in the context of the neuroanatomy and neurochemistry of cardiorespiration and arousal. Quantitative abnormalities in brainstem reactive astrocytes (scar cells), dendritic spines, and neurotransmitter levels, and number of small myelinated vagal fibers have been reported in SIDS. The cause of these abnormalities is not known, nor is their relationship to each other or sudden death clear. Their complete elucidation, however, is perhaps the most compelling reason for continued SIDS brainstem research, since such abnormalities could be the critical clues necessary for solving SIDS.