Lower extremity infections are frequent causes of substantial morbidity and mortality in the diabetic population, and these infections consume a large portion of resources expended on diabetic complications. Gram-positive cocci, particularly Staphylococcus aureus, are the most important pathogens in diabetic foot infections. These organisms are predominant both in mild infections (which are often monomicrobial), as well as in more severe and chronic infected wounds that more often have a polymicrobial cause. Appropriate clinical assessment and culturing of infections are critical in establishing the presence and severity of infection, in detecting osteomyelitis, and in directing the optimal treatment approach. Following necessary debridement and other surgical interventions (e.g., bone resection, revascularization), appropriate antibiotic therapy is a cornerstone of managing the infected lower extremity. Peripheral vascular (i.e., arterial) insufficiency and the increasing prevalence of antibiotic resistance are primary barriers to successfully managing these infections. Fortunately, alternative delivery systems (e.g., antibiotic beads, impregnated sponges) and novel antibiotics (e.g., levofloxacin, linezolid) are providing possible solutions to the challenges posed by this physically, emotionally, and financially devastating condition.