Recent advances in genomics, proteomics, bioinformatics and systems biology have unraveled the complex aberrant signaling networks in cancer. The knowledge accrued has dramatically increased the opportunities for discovery of novel molecular targets for drug development. Major emphasis is being laid on designing new therapeutic strategies targeting multiple signaling pathways for more effective disease management. However, the translation of in vitro findings to patient management often poses major challenges that limit their clinical efficacy. Here we will discuss how understanding the dysregulated signaling networks can explain the pitfalls in translating the laboratory findings from the bench-to-bedside and suggest novel approaches to overcome these problems using head and neck cancer as a prototype. The five year survival rates of HNSCC patients (about 50% at 5 years) have not improved significantly despite advancements in multimodality therapy including surgery, radiation and chemotherapy. Molecular targeted therapies with inhibitors of EGFR and VEGF either alone, or in combination with conventional treatments have shown limited improved efficacy. The key deregulated signaling pathways in head and neck squamous cell carcinoma (HNSCC) include EGFR, Ras, TGFbeta, NFkappaB, Stat, Wnt/beta-catenin and PI3-K/AKT/mTOR. The aberrant activities of these interrelated signaling pathways contribute to HNSCC development. In depth understanding of the cross-talks between these pathways and networks will form the basis of developing novel strategies for targeting multiple molecular components for more effective prevention and treatment of HNSCC.