AbstractFrom the earliest publications on cot death or sudden infant death syndrome (SIDS) through to this day, clinical pathology and epidemiology have strongly featured infection as a constant association. Despite mounting evidence of the role of viruses and common toxigenic bacteria in the pathogenesis of SIDS, a growing school of thought featuring a paradigm based on the triple risk hypothesis that encompasses vulnerability through deranged homoeostatic control of arousal and/or cardiorespiratory function has become the mainstream view and now dominates SIDS research. The mainstream hypothesis rarely acknowledges the role of infection despite its notional potential role as a cofactor in the triple hit idea. Decades of mainstream research that has focussed on central nervous system homoeostatic mechanisms of arousal, cardiorespiratory control and abnormal neurotransmission has not been able to provide consistent answers to the SIDS enigma. This paper examines the disparity between these two schools of thought and calls for a collaborative approach.ImpactThe popular research hypothesis explaining sudden infant death syndrome features the triple risk hypothesis with central nervous system homoeostatic mechanisms controlling arousal and cardiorespiratory function. Intense investigation has not yielded convincing results. There is a necessity to consider other plausible hypotheses (e.g., common bacterial toxin hypothesis).The review scrutinises the triple risk hypothesis and CNS control of cardiorespiratory function and arousal and reveals its flaws.Infection-based hypotheses with their strong SIDS risk factor associations are reviewed in a new context.