Despite advances in multimodality therapies for the treatment of squamous cell carcinoma of the head and neck (SCCHN), survival rates, functional outcomes and toxicities of therapy remain poor. The recognition of the prognostic value of human papillomavirus (HPV) status, and the advent of biologically targeted therapies with potential for decreased toxicities and increased selectivity, represent significant developments in our understanding of SCCHN. Targeted agents currently approved or under investigation for SCCHN include epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab, panitumumab, zalutumumab, nimotuzumab), EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib, afatanib, dacomitinib), vascular endothelial growth factor receptor (VEGFR) inhibitors (bevacizumab, sorafenib, sunitinib, vandetanib) and various inhibitors of other pathways and targets, including phosphatidylinositol 3' kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), MET and insulin-like growth factor receptor (IGF-1R). On-going clinical trials are evaluating these emerging agents and their combinations in the treatment of SCCHN.