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Sepsis is a major cause of morbidity and mortality in the United States and remains the leading cause of death in children worldwide. Children with sepsis and progressive septic shock present a unique set of challenges for clinicians as the diagnosis, initial fluid resuscitation, and subsequent hemodynamic support are different to those in the adult population. The most common pathogens identified in children are bacterial in origin. Susceptibility, progression, and the overall clinical course of sepsis in children are influenced by factors from both the host immune response and innate defense systems as well as virulence factors specific to the pathogen. While in adults, diagnosis has shifted toward clinical models of end-organ dysfunction, the systemic inflammatory response syndrome (SIRS) criteria remain the mainstay in diagnosis of pediatric sepsis. In this chapter, we discuss the incidence, host and pathogen risk …