A common definition of sepsis is necessary to identify patients with sepsis in clinical practice, to enroll patients into prospective research studies, and to conduct surveillance and retrospective research. However, defining sepsis has proven challenging. Sepsis has generally been conceptualized as an injurious host response to infection. Modern definitions have evolved from defining this injurious host response as a systemic inflammatory response to life-threatening acute organ dysfunction. While current sepsis definitions have several limitations, including the lack of a gold standard and tremendous heterogeneity of presentations, ongoing research offers promise to improve sepsis diagnosis and future definitions.