ABSTRACT: Improving time to diagnosis and intervention has positively impacted outcomes in acute myocardial infarction, stroke, and trauma through elucidating the early pathogenesis of those diseases. This insight may partly explain the futility of time-insensitive immunotherapy trials for severe sepsis and septic shock. The aim of this study was to examine the early natural history of circulatory biomarker activity in sepsis, relative to previous animal and human outcome trials. We conducted a literature search using PubMed, MEDLINE, and Google Scholar to identify outcome trials targeting biomarkers with emphasis on the timing of therapy. These findings were compared with the biomarker activity observed over the first 72 h of hospital presentation in a cohort of severe sepsis and septic shock patients. Biomarker levels in animal and human research models are elevated within 30 min after exposure to an inflammatory septic stimulus. Consistent with these findings, the biomarker cascade is activated at the most proximal point of hospital presentation in our patient cohort. These circulatory biomarkers overlap; some have bimodal patterns and generally peak between 3 and 36 h while diminishing over the subsequent 72 h of observation. When this is taken into account, prior outcome immunotherapy trials have generally enrolled patients after peak circulatory biomarker concentrations. In previous immunotherapy sepsis trials, intervention was delayed after the optimal window of peak biomarker activity. As a result, future studies need to recalibrate the timing of enrollment and administration of immunotherapy agents that still may hold great promise for this deadly disease.