This article reviews principles in the rational use of antibiotics in sepsis and septic shock and presents evidence-based recommendations for optimal antibiotic therapy. Every patient with sepsis and septic shock must be evaluated at presentation before the initiation of antibiotic therapy. However, in most situations, an abridged initial assessment focusing on critical diagnostic and management planning elements is sufficient. Intravenous antibiotics should be administered as early as possible, and always within the first hour of recognizing severe sepsis and septic shock. Broad-spectrum antibiotics must be selected with one or more agents active against likely bacterial or fungal pathogens and with good penetration into the presumed source. Antimicrobial therapy should be reevaluated daily to optimize efficacy, prevent resistance, avoid toxicity, and minimize costs. Consider combination therapy in Pseudomonas infections, and combination empiric therapy in neutropenic patients. Combination therapy should be continued for no more than 3 to 5 days and deescalation should occur following availability of susceptibilities. The duration of antibiotic therapy typically is limited to 7 to 10 days; longer duration is considered if response is slow, if there is inadequate surgical source control, or in the case of immunologic deficiencies. Antimicrobial therapy should be stopped if infection is not considered the etiologic factor for a shock state.