Sepsis-associated cardiac arrest is a relatively common occurrence with especially poor outcomes. Of the greater than 200,000 in-hospital cardiac arrests that occur in the United States annually, between 30,000 and 60,000 occur in patients with underlying sepsis. These patients are less likely to survive than cardiac arrest victims without sepsis. In this review, we discuss the epidemiology of sepsis-associated in-hospital cardiac arrest in adults and children, the relevant physiology responsible for its pathogenesis and poor outcomes, and potential therapeutic interventions based on this pathophysiology. We postulate that persistence of sepsis pathophysiology during and after cardiac arrest is responsible for these poor outcomes. This includes derangements of vascular tone and intravascular volume status; myocardial dysfunction; hypoxemia, acidemia, and other metabolic derangements; and pulmonary hypertension. Potential interventions that specifically target this pathophysiology before, during, and after cardiac arrest may augment standard cardiopulmonary resuscitation and post-resuscitation care for patients with sepsis and septic shock.