The word, sepsis, dates back more than 2 millennia but has, over the past 2 centuries, come to be applied first to the clinical state evoked by invasive infection and, more recently, to describe the syndrome resulting from the host response to infection. Further refinements embodied in the recently published Sepsis-3 definition underline the concept of a dysregulated immune response resulting in potentially modifiable life-threatening organ dysfunction. This review summarizes the evolution and limitations of efforts to characterize a common and complex disorder.