This chapter discusses immunology and immunotherapy, where head and neck squamous cell carcinoma (HNSCC) comprises 80 percent of cancers involving the upper aerodigestive tract with the main etiologies being tobacco and alcohol consumption. The theory of immunosurveillance postulates that the immune system composed of effector cells and associated molecules can recognize and eradicate neoplastic cells, thereby preventing tumor formation. The immune system is a complex one in which the body uses effector cells and humoral mediators to react to exogenous and endogenous antigens recognized as foreign. The immune system is divided into natural or innate and acquired or specific immune systems. T cells can serve as specific and nonspecific cytotoxic effectors and mobile cytokine factories that can be redirected using bispecific antibodies (BiAb) or engineered chimeric receptors to target specific tumor-associated antigens (TAA).