Septic shock affects 750,000 people annually, and accounts for 10 % of all deaths annually in the US. In recent years, outcomes in patients with septic shock have improved; however, mortality still remains high at 40 - 50 %. The use of early protocolized resuscitation goals have been associated with reduced mortality in septic shock. However, strong evidenced-based recommendations for the continued management of patients with septic shock in the ICU setting are currently lacking. Appropriate antibiotic therapy is the cornerstone of management in septic shock. Inappropriate antibiotic therapy can lead to treatment failures and adverse outcomes, including high risk of mortality. This article outlines other key factors that contribute to outcome in septic shock. It is challenging for physicians to optimize therapy when fixed patient features such as age and underlying comorbidity can negatively influence mortality. However, outcomes can also potentially be affected by physician management decisions including fluid balance, corticosteroid use, glucose control and adherence to protocols including early goal-directed therapy and infection-control measures. Certain pathogen virulence characteristics also adversely affect outcomes. We give an overview of the determinants of outcome in septic shock in the setting of appropriate antibiotic use.