Although cancers arising in the head and neck region are a diverse group of malignancies, a unifying thread remains a poor overall survival for patients with advanced, recurrent or metastatic disease. Treatment strategies need to evolve and improve upon established therapeutic practices. As the process of cancer evolution is understood to be derived from aberrations in genetic and epigenetic processes, molecularly targeted agents offer attractive therapeutic options by restoring normal control of oncogenic processes. The direct role for the treatment of squamous cell carcinoma of the head and neck, nasopharynx and salivary gland carcinomas with these novel, molecularly targeted agents are reviewed and their potential to improve on the existing standard of care is further explored.