Initial antibiotic therapy for diabetic foot infections is usually empirical. Several principles may help to avoid selecting either an unnecessarily broad or inappropriately narrow regimen. First, clinically severe infections require broad-spectrum therapy, while less severe infections may not. Second, aerobic Gram-positive cocci, particularly Staphylococcus aureus (including methicillin-resistant S. aureus (MRSA) for patients at high-risk) should always be covered. Third, therapy should also be targeted at aerobic Gram-negative pathogens if the infection is chronic or has failed to respond to previous antibiotic therapy. Fourth, anti-anaerobe agents should be considered for necrotic or gangrenous infections on an ischaemic limb. Parenteral therapy is needed for severe infections, but oral therapy is adequate for most mild or moderate infections.