Diabetic foot infections cause substantial morbidity, incur significant costs, and may lead to amputation. Resistant organisms, particularly methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant gram-negative organisms, are becoming more prevalent. Optimal management of diabetic foot infections is multimodal, and includes not only antimicrobial therapy but also biomechanical support and offloading, local wound care, glycemic control, assessment and treatment of underlying vascular disease, and surgical therapy when warranted. Antimicrobial therapy should be targeted at the likely etiologic agents and should take into consideration the depth and severity of infection. With expansion of the reservoir of resistant organisms, obtaining reliable deep cultures can help focus antimicrobial therapy against the dominant pathogens. Newer agents against resistant gram-positive and gram-negative organisms show promise in the treatment of diabetic foot infections.