Increased attention has focused recently on the acute management of severe sepsis and septic shock, conditions that represent the end-stage systemic deterioration of overwhelming infection. Clinical trials have identified new therapies and management approaches that, when applied early, appear to reduce mortality. Practice guidelines have been advanced by critical care societies, and many of the proposed interventions involve therapies other than antimicrobials directed at hemodynamic resuscitation or addressing adverse effects of the inflammatory cascade. Although many emergency departments (EDs) are now adopting treatment protocols for sepsis that are based on published treatment guidelines, recent research calls many of the initial recommendations into question, and validation trials of some of these approaches are ongoing. This article reviews the initial evaluation and treatment considerations of sepsis in the ED setting.