The role of microorganisms in the etiology and persistence of chronic wounds remains poorly understood. The chronic wound bed houses a complex microenvironment that typically includes more than one bacterial species. Difficulty lies in determining when the presence of bacteria impedes wound healing, thereby warranting intervention. Indications for antibiotic therapy and optimal treatment regimens are ill defined. The goal of this article is to describe the appropriate role of systemic antibiotics in the management of chronic wounds. A common sense approach will be offered based on six clinically pertinent questions: Is infection present? Are systemic antibiotics necessary? Should treatment be enteral or parenteral? What antibiotic or combination of antibiotics should be used? What should be the duration of therapy? What special circumstances are present (i.e., concomitant illnesses, potential drug-drug interactions) that can impact therapy?