Monoclonal antibodies (mAbs) are now commonly used therapeutic agents in cancer patients. Since US Food and Drug Administration approval of cetuximab for head and neck squamous cell carcinoma, it has been used increasingly in this disease. Several other mAbs also are in development or in clinical -trials. Recently, evidence has accumulated that mAbs induce activation of cellular immunity, including natural killer and T cells and that this may contribute to clinical response. mAbs have been shown to mediate antibody-dependent cellular cytotoxicity, complement-dependent lysis, and activation of tumor antigen-specific T cells. Various patient and tumor factors, such as polymorphisms in Fcgamma receptors expressed by immune cells, activity of T-regulatory cells, and tumor escape through downregulation of antigen-processing machinery in tumor cells, are likely to modulate the immune activation mediated by therapeutic mAbs. Understanding the interplay of these factors is likely to improve the selection of the most appropriate candidates for mAb-based immunotherapy, prediction of clinical response, and our understanding of mechanisms of tumor escape from therapeutic mAbs.