Induction therapy followed by definitive chemoradiotherapy (CRT) has emerged as an option for the treatment of patients with locally advanced squamous cell carcinoma of the head and neck. In this setting, the most studied induction regimen is docetaxel, cisplatin, and 5-fluorouracil (TPF). However, the role of induction therapy remains to be fully validated by studies comparing TPF followed by CRT versus CRT alone. Novel combination regimens that incorporate molecularly targeted agents are increasingly being evaluated in the induction therapy setting. Promising results were shown in phase II trials in which the anti-epidermal growth factor receptor monoclonal antibody cetuximab was added to induction therapy with TPF, docetaxel/cisplatin, or paclitaxel/carboplatin, and in some of these studies, to subsequent CRT. Several issues remain to be addressed, including identifying which patients are most likely to benefit from induction therapy, determining how to optimally incorporate targeted agents into induction therapy and subsequent CRT, and evaluating biomarkers that could be used to select patients for induction therapy containing molecularly targeted agents.