Infection represents the presence of an inflammatory response and tissue injury due to the interaction of the host with multiplying bacteria. The disease spectrum is a consequence of the variability in these interactions. Diabetes, because of its effects on the vascular, neurological, and immune systems, can compromise the local and systemic response to infection, potentially masking the typical clinical features and hindering diagnosis. The early recognition of infection, particularly osteomyelitis, is paramount in the management of diabetic foot disease. Careful clinical appraisal remains the cornerstone of the assessment. Hematologic, biochemical, and radiological investigations are important aids in assessing the severity of infection. Microbiological assessment, particularly in more severe infection, requires good-quality samples, combined with rapid transport in an appropriate medium and effective communication with the laboratory. A focused, systematic approach to the accurate diagnosis and treatment of infection, combined with careful monitoring, ensures the maintenance of optimal management.