Immune system function and dysfunction have been shown to play a larger role than thought previously in many disease processes. Autoimmune diseases such as juvenile idiopathic arthritis (JIA) and chronic recurrent multifocal osteomyelitis are regularly treated by the oral and maxillofacial surgeon. Modification of immune response has a vital role in therapy for these conditions. In addition, head and neck cancer has been shown to inhibit local immune function. The presence of immune infiltrates within a tumor may predict outcome in head and neck squamous cell carcinoma (HNSCC). Immunotherapies may have a synergistic role with operative management and could be the future of biomarker directed personalized treatment of HNSCC.