Sepsis is a significant cause of death worldwide. Although the prevailing theory of the sepsis syndrome has been that of a condition of uncontrolled inflammation in response to infection, sepsis is increasingly being recognized as an immunosuppressive state. The immune modulations of sepsis result in altered innate and adaptive immune responses, thereby rendering the septic host susceptible to secondary infections. In this review, we present an overview of the clinical and experimental evidence for sepsis-induced immunosuppression and outline the mechanisms that underlie this phenotype. With an improved understanding of how host immune states may be altered during sepsis, better immunomodulatory therapies may be developed to address the immune derangements observed in patients with sepsis.