Advances in the management of patients with head and neck squamous cell carcinoma (HNSCC) have not significantly changed the prognosis of this tumor over the past five decades. Molecular heterogeneity of HNSCC and its association with HPV, in addition to the increase in the number of cancers arising in traditionally low-risk patients, are among some of the obstacles to the successful management of this group of tumors. Massively parallel sequencing, otherwise known as next-generation sequencing (NGS), is rapidly changing conventional patient management by providing detailed information about each patient's genome and transcriptome. Despite major advances in technology and a significant reduction in the cost of sequencing, NGS remains mainly limited to research facilities. In addition, there are only a few published studies that have utilized this technology in HNSCC. This paper aims to report briefly on current commercially available NGS platforms and discuss their clinical applications, ethical considerations, and utilization in personalized patient care, particularly as this relates to head and neck cancer.