Appendicular musculoskeletal infections can affect individuals of any age. They include infections of osseous and extra-osseous tissues. Their most common presentations are osteomyelitis (acute, subacute, or chronic), septic arthritis, soft tissue infections (cellulitis, fasciitis, abscess, and pyomyositis), implant infection, and diabetic foot infection. Most of the appendicular musculoskeletal infections are bacterial, with Staphylococcus aureus being the most common pathogen, while fungal and parasitic infections are less frequent. Tuberculosis and brucellosis are still endemic in certain parts of the world. Healthy musculoskeletal tissue exhibits a robust resistance to infection. However, certain conditions can tip the balance in favor of bacterial colonization and infection, through hematogenous spread or direct invasion. Appendicular musculoskeletal infections need early diagnosis and appropriate management to prevent long-term morbidity. Clinical diagnosis is difficult, particularly in the early stages of infection where the clinical picture is often confusing. Recent improvements in culture detection methods and implementation of sensitive nucleic acid amplification tests have greatly enhanced the laboratory diagnosis of these infections. However, microbiological diagnosis remains challenging due to several factors, e.g., prolonged presence of certain antibiotics in bone tissue, diverse range of involved species, reduced metabolic activity of bacteria in chronic infections, and difficulty in obtaining adequate sample material for analysis. This chapter describes the pathophysiology and microbiological diagnosis of the various appendicular musculoskeletal infections.