Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with 300,0000 deaths and 550,0000 new cases reported every year. Lack of targeted treatments have led to poor survival rate in this cancer with current five-year survival rate around 50%, which has changed only marginally in the past few decades. Current methods of patient stratification and treatments largely relies on conventional non-molecular approaches, without considering the high level of heterogeneity in genetic and molecular profile unveiled in head and neck cancer patients. Our lab has previously elucidated a novel GRHL3/GSK3B/c-Myc signaling axis in HNSCC. Bromodomain inhibition has demonstrated potent anti-tumour effect in various cancers. I-BET 151 is a small molecule inhibitor that perturbs c-Myc transcription by abrogating bromodomain recruitment to chromatin. We hypothesized that targeting c-Myc using I-BET-151 would be a potential approach in treating HNSCC. Efficacy of the drug was analyzed in diverse HNSCC experimental models including HNSCC cell lines and mice models. I-BET 151 effectively reduced proliferation and clonogenic capacity of the cancer cell lines in-vitro. Reduced tumour growth and improved overall survival were observed in drug treated orthotopic xenograft mice models especially in those grafted with c-Myc dependent cell lines. In carcinogen treated models, treatment with IBET-151 significantly reduced tumour burden and increased tumour free survival in WT mice whereas no such benefit was observed in Grhl3 conditional knockout mice. Extend of c-Myc dependency correlated with the drug effectiveness and this strategy could be applied in developing personalized therapies. Although targeting the GRHL3/GSK3B/c-Myc axis holds promise in HNSCC, pathway cross-talk and functional compensation from inhibiting single pathway members must be investigated prior to incorporating such therapeutic agents in to routine clinical care.