Appendicular musculoskeletal infections include osseous and extraosseous infections. Skeletal infections need early diagnosis and appropriate management to prevent long-term morbidity. The diagnosis of appendicular musculoskeletal infections relies on the culture of causative organisms and histopathological data from a biopsy sample. Prior to biopsy, review of the relevant clinical history and pertinent imaging is mandatory. Percutaneous imaging-guided biopsy of bone and soft tissue lesions is a cost-effective and accurate method to obtain a histopathologic diagnosis. Biopsy requests must be approached thoughtfully to avoid numerous potential pitfalls. The biopsy route must be planned in concert with the referring clinician. Carefully selecting the most appropriate imaging modality to guide the biopsy increases the chances of reaching a definitive diagnosis.