Despite recent advancements in treatment modalities, the overall survival and quality of life of patients with head and neck squamous cell carcinoma (HNSCC) have not significantly improved over the past decade. With the increasing emergency of new biological agents, the development of novel treatment schemes based on cancer cell biology may be promising for this group of patients. We previously introduced the “oncogene addiction” concept as a rationale for molecular targeting in cancer therapy and prevention. In this context, an increasing number of preclinical studies have demonstrated that the Signal Transducers and Activators of transcription 3 (Stat3) transcription factor play critical roles in the development and progression of a variety of tumors including HNSCC, by regulating cell proliferation, cell cycle progression, apoptosis, angiogenesis, immune evasion, Epithelial-Mesenchymal Transition (EMT) and through effects in cancer stem cells. The purpose of this review is to summarize current experimental and clinical evidence that suggests that HNSCC might be addicted to Stat3 and describes the molecular mechanisms that may explain this phenomenon. In addition, we discuss whether this addiction is an exploitable target for developing approaches for the treatment and prevention of HNSCC.