Squamous cell carcinoma of head and neck (SCCHN) is the sixth most common malignancy and is a major cause of cancer morbidity and mortality worldwide. As with most solid cancers, the cure rate for SCCHN is excellent if tumors are diagnosed early in the course of the disease. Early diagnosis of cancer remains difficult because of the lack of specific symptoms in early disease as well as the limited understanding of etiology and oncogenesis. Advances in proteomics and genomics contribute to the understanding of the pathophysiology of neoplasia, cancer diagnosis and anticancer drug discovery. The powerful 'omics' technologies have opened new avenues towards biomarker discovery, identification of signaling molecules associated with cell growth, cell death, cellular metabolism and early detection of cancer. Analysis of tumor-specific omics profiles provided a unique opportunity to diagnose, classify, and detect malignant disease; to better understand and define the behavior of specific tumors; and to provide direct and targeted therapy. These technologies however still require integration and standardization of techniques and validation against accepted clinical and pathologic parameters. This article provides a summary of technologies, potential clinical applications, and challenges of omics in head and neck cancer.