Sudden death, defined as an unexpected, natural death occurring within one hour of symptom onset or within 24 hours of the person's last being seen alive and well, remains one of medicine's most devastating events. It accounts for approximately 10-15% of all global deaths and presents a persistent challenge to healthcare systems worldwide. The term "Sudden Death Syndrome" (SDS) encompasses multiple etiologies, with the most common being Sudden Cardiac Death (SCD) in adults and Sudden Infant Death Syndrome (SIDS) in infants under one year of age.

In adults, SCD is frequently the first and only manifestation of underlying cardiovascular disease, often occurring in individuals with no prior symptoms or diagnosed conditions. Traditional risk stratification relies heavily on left ventricular ejection fraction (LVEF), yet this parameter has limited sensitivity, as the majority of SCDs occur in individuals with preserved ejection fraction. In infants, despite significant reductions in SIDS incidence following safe sleep campaigns in the 1990s, rates have since plateaued, with 50-70% of sudden unexpected infant deaths remaining unexplained after complete post-mortem investigation.

The current reactive paradigm—where investigation begins only after death—limits opportunities for prevention. This has driven interest in biomarkers as tools that offer a window into underlying pathophysiology. Biomarkers can serve multiple purposes: early risk stratification in living individuals, clarification of cause of death in post-mortem settings, and guidance for family screening when inherited conditions are suspected.

This systematic review aims to: (1) map the biomarker landscape across SDS etiologist, (2) evaluate the clinical utility of identified biomarkers, (3) propose an integrated multi-modal assessment framework, and (4) translate findings into practical implications for clinical and forensic practice.