Histopathological examination obtained by biopsy or surgical excision is important for the diagnosis of appendicular infections for two reasons. Firstly, histopathology allows ruling out noninfectious diseases, mainly lesions of tumor origin; and secondly, it offers direct microscopical evaluation of the tissue and direct morphological assessment of possible infectious agents. The inflammatory response to the causative agents is sufficiently consistent and predictable, allowing the pathologist to identify an infectious process and to suggest the causative agent (bacteria, mycobacteria, fungi, or parasite). The hallmark histopathological finding of pyogenic appendicular musculoskeletal infections is suppurative inflammation, frequently observed in acute forms of pyogenic infections. Pyogenic chronic bone infection is characterized by marrow fibrosis with chronic inflammatory cells, focal bone necrosis, and reactive bone formation. The bone cortex may be broken down, and pus may reach adjacent soft tissues to form abscesses and sinus tracts. But the pathologist must be aware that acute and chronic forms of osteomyelitis are clinical and radiological entities and that the macroscopical and microscopical features of inflammatory reactions in these entities may overlap. As in other locations, histological examination of appendicular musculoskeletal tuberculosis shows epithelioid cell granulomas, some with central caseous necrosis. The gold standard for the diagnosis of tuberculosis is the identification of acid-fast bacilli by Ziehl-Neelsen stain. However, because of the low load of bacilli at the infected sites, Ziehl-Neelsen stain is often negative and a typical granulomatous reaction will guide the diagnosis and management. In individuals with advanced immunosuppression, there is a striking paucity of granuloma formation with little cellular recruitment. But lesions are generally rich in bacilli. Histopathology plays an important role in the diagnosis of appendicular musculoskeletal fungal infections. It allows a rapid diagnosis, compared to culture. Moreover, microbiological studies might not be available because the sample might have been fixed in its entirety. The pathologist may, by analyzing the infected tissue, identify the fungus and assess the induced tissue reaction. Fungal infections display a large spectrum of microscopical lesions. Histological clues suggesting fungal infection are (1) pyogranulomatous inflammation consisting of suppurative inflammation admixed with often poorly defined and giant cell-rich granulomas; (2) necrotizing and granulomatous inflammation, mimicking mycobacterial infections; and (3) necrotizing inflammation with necrotizing vasculitis through infiltration and necrosis of vessels by fungal organisms. Fungal agents may be identified in tissue sections with routine hematoxylin and eosin stain, but special stains such as periodic acid-Schiff and Grocott methenamine silver help in their identification and offer better morphological assessment. Hydatid disease, also called echinococcal disease, is the most frequent parasitic appendicular musculoskeletal infection in our locality. Hydatid disease resulting from infestation with Echinococcus granulosus is the most frequent form. Bone hydatid disease does not resemble the classic unilocular hydatid cysts of soft tissues. In bone involvement, pericyst formation does not occur. The cysts percolate between the trabeculae, and outlines of the lesion are irregular with no obvious sclerosis or periosteal reaction. Moreover, due to the absence of pericyst, bone cysts rarely demonstrate calcification, unlike extra-osseous cysts which may calcify. The typical appearance of the membrane forming the parasitic cysts is easily recognized grossly and microscopically as belonging to hydatid cyst and allows the diagnosis. Grossly, the membrane is about 1 mm thick. It is whitish, slightly opaque, smooth, and ropy. In histological sections, it appears as homogeneous, often slightly laminated red strips, which show up very brightly with hematoxylin and eosin staining.