The advent of modern antimicrobial therapy following the discovery of penicillin during the 1940s yielded remarkable improvements in the case fatality rates of serious infections, including septic shock. Since then, pathogens have continuously evolved under selective antimicrobial pressure, resulting in a lack of additional significant improvement in clinical effectiveness of antimicrobial therapy of septic shock despite ever more broad-spectrum and potent drugs. In addition, although substantial effort and money were expended on the development of novel nonantimicrobial therapies of sepsis in the past 30 years, clinical progress in this regard has been limited. This article explores the possibility that the key to significant improvement in the outcome of septic shock may lie, in great part, with improvements in delivery of existing antimicrobials. Recognizing the role of delays in administration of antimicrobial therapy in the poor outcomes of septic shock is central to this effort.