Biomedical scientists are aggressively investigating biomarkers of disease and injury. The rationale for identifying biomarkers during pathological states, such as severe sepsis, is to improve clinical prognostication and stratify therapeutic interventions for optimal recovery. An added benefit of biomarker studies is knowledge genesis on pathophysiological mechanisms, critical information that provides a basis for hypothesis-driven research. Unfortunately, biomarkers rarely alter our clinical approach in severe sepsis as they are often non-specific, lack adequate sensitivity and/or are difficult to measure and interpret accurately. Given the complexity and heterogeneity of severe sepsis, and the unique genetically derived susceptibilities of individuals, it is highly unlikely that one or even a handful of biomarkers will provide adequate biomedical information for clinical guidance. Thus, biomarkers will ultimately alter clinical decision making only once a panel of promising biomarkers is identified, maximizing sensitivity and specificity, and then adequately scrutinized with quantitative scoring methods over large populations of patients.