This chapter presents a state of the art summary of histolytic and dendritic cell neoplasms to its biology, epidemiology, disease mechanisms, clinical signs, diagnosis, treatment and prognosis. Derived from myeloid stem cell/monoblasts, dendritic cells, monocytes, macrophages, and histiocytes are members of the mononuclear phagocyte system. Derived from stromal cells located in the follicles of activated lymph nodes, follicular dendritic cells accumulate and entrap immune complexes and store antigens that serve as a nidus for B-cell proliferation and differentiation with help from T-cells. Indeterminate dendritic cell tumor is restricted to the skin without systemic symptoms. Treatment options for histiocytic and dendritic cell neoplasms consist of surgical resection, chemotherapy, and/or radiotherapy. The etiology of dendritic and histiocytic cell neoplasms is currently unknown, although some types harbor BRAF mutations. Human dendritic cells comprise two groups: plasmacytoid and myeloid. Follicular dendritic cell sarcoma usually manifests as a slow-growing mass in the head and neck or abdominal lymph nodes.