The integration of targeted therapies such as cetuximab to radiation therapy has revolutionized the management of head and neck cancers in the last decade. However, the use of targeted therapies raised several clinically relevant questions that have yet to be answered. These questions include the optimal patient and tumor profile for biologically targeted therapy, the optimal radiation fractionation to use with targeted therapies, how to integrate them into standard or new chemoradiation regimens, their schedule and duration of administration, their toxicity, and which direction to consider for novel targeted treatment. In this review, we highlight several of these important issues, discuss the clinical trials that are designed to address these issues, and introduce some novel targeted therapies that may contribute to the improvement of the therapeutic ratio for head and neck cancer therapy.