Sepsis is a common and severe medical condition with substantial associated morbidity, mortality and cost. Furthermore, the incidence of sepsis has been rising annually over the past three decades, and morbidity and mortality remain high. The management of sepsis is further complicated by its very heterogeneous nature. This extends not only to the offending pathogens, but also to the nature and severity of the host response as well as its clinical manifestations. Efforts to identify surrogate markers for sepsis have therefore been an ongoing struggle. In this article we present some insights into various sepsis markers through history, presenting advantages and caveats associated with their use and interpretation. We also discuss the state of functional genomics, a relatively recent technological advancement that has already begun to change our understanding of sepsis pathophysiology, and offer new directions in the development of a more sensitive and specific sepsis biomarker.