Antibiotic therapy is not the most important component in diabetic foot ulcer management which should be based on weight bearing avoidance and arterial revascularization. However antibiotic therapy is necessary in presence of extensive deep involvement or systemic signs of infection. Initial antimicrobial treatment depends on bacteria supposed origin. For patients not coming from hospital, the initial choice antibiotic is an amoxicillin/clavulanate agent because it offers optimal coverage for most pathogens involved in those diabetic foot lesions (gram positive cocci, gram negative and anaerobic organisms). For patients at high risk to be infected with nosocomially acquired pathogens, the initial antibiotic therapy must cover methicillin-resistant staphylococci, resistant pseudomonas aeruginosa or enterobacteriae. In all cases, when definitive reliable cultures are reported, initial antibiotic regimens should be revised to narrow the coverage to specific pathogens. In presence of osteomyelitis, a temporary combination of two agents which are known to reach high bone concentrations is necessary, and antibiotic therapy should be continued for at least two months. In other cases, antibiotic treatment duration depends on clinical out come.