Molecular targeted therapy in head and neck squamous cell carcinoma (HNSCC) continues to make strides, and holds much promise. Cetuximab remains the sole US FDA-approved molecular targeted therapy available for HNSCC, though several new biologic agents targeting the epidermal growth factor receptor (EGFR) and other pathways are currently in the regulatory approval pipeline. While targeted therapies have the potential to be personalized, their current use in HNSCC is not personalized. This is illustrated for EGFR-targeted drugs, where EGFR as a molecular target has yet to be individualized for HNSCC. Future research needs to identify factors that correlate with response (or lack of one) and the underlying genotype-phenotype relationship that dictates this response. Comprehensive exploration of genetic and epigenetic landscapes in HNSCC is opening new frontiers to further enlighten and mechanistically inform newer as well as existing molecular targets, and to set a course for eventually translating these discoveries into therapies for patients. This opinion offers a snapshot of the evolution of molecular subtyping in HNSCC and its current clinical applicability, as well as new emergent paradigms with implications for controlling this disease in the future.