Histiocytic sarcoma, a rare malignant neoplasm showing morphologic and immunophenotypic features of histiocytes, is characterized typically by extranodal presentation and a dismal clinical course, particularly in patients with disseminated disease. A history of hematolymphoid disorder can be identified in a subset of patients, suggesting transdifferentiation of a preexisting hematolymphoid neoplasm in its pathogenesis. The differential diagnosis of histiocytic sarcoma includes various lymphomas, other histiocytic and dendritic cell neoplasms, carcinomas, melanomas, and pleomorphic sarcomas. Given its rarity and histologic overlap with diverse mimics, the diagnosis of histiocytic sarcoma can be extremely challenging. Recognition of morphologic clues, as well as judicious application of immunohistochemical markers to confirm its histiocytic lineage and to exclude mimics, is crucial for the diagnosis. Recent molecular studies by targeted next-generation sequencing identified recurrent alterations in the mitogen-activated protein (MAP) kinase pathway and chromatin regulators in the pathogenesis of histiocytic sarcoma and may suggest possible therapeutic targets.