BACKGROUND: Decades of mainstream SIDS research based on the Triple Risk Model and neuropathological findings have failed to provide convincing evidence for a primary CNS-based mechanism behind putative secondary dyshomeostasis (respiratory or cardiac) or impaired arousal. Newly revealed data indicate that severe metabolic acidosis (and severe hyperkalemia) is a common accompaniment in SIDS. This supports the direct effect of sepsis on vital-organ function and occurrence of secondary CNS changes accompanied by the dyshomeostasis leading to SIDS. DATA SOURCES: Using PubMed and Google Scholar literature searches, this paper examines how metabolic acidosis and sepsis might contribute to the underlying pathophysiologic mechanisms in SIDS. RESULTS: The discovery of a series of non-peer-reviewed publications provided the basis for a serious examination of the role of metabolic acidosis and sepsis in SIDS. Most SIDS risk factors relate directly or indirectly to infection. This consequently elevated the position of septic or superantigenic shock and viremia in causing secondary organ failure leading to SIDS. The latter could include diaphragmatic failure, as evidenced by peripheral respiratory (muscle) arrests in experimental septic shock, as well as infectious myositis and diaphragm myopathy in sudden unexpected deaths, including SIDS. In addition, just as acidosis lowers the threshold for ventricular fibrillation and sudden cardiac arrest, it could also contribute to similarly unstable diaphragm excitation states leading to respiratory failure. CONCLUSIONS: This paper uniquely reveals compelling evidence for a connection between metabolic acidosis, sepsis, viral infections, and sudden unexpected child deaths and provides a solid basis for further work to define which pathway (or pathways) lead to the tragedy of SIDS. It is recommended that all autopsies in sudden unexpected deaths should include pH, bicarbonate, lactate, and electrolyte measurements, as well as diaphragm histology.