Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis‐induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti‐inflammatory responses. With advances in intensive care medicine and goal‐directed interventions, early 30‐day sepsis mortality has diminished, only to steadily escalate long after “recovery” from acute events. As so many sepsis survivors succumb later to persistent, recurrent, nosocomial, and secondary infections, many investigators have turned their attention to the long‐term sepsis‐induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis‐associated immune cell defects correlate with long‐term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long‐term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long‐term sepsis mortality.