Cancer stem cells (CSCs), or tumor-initiating cells, comprise a subset of tumor cells with demonstrated ability for tumor growth, invasion, metastasis, and resistance to chemotherapy and radiation. Targeting of CSCs remains an attractive yet elusive therapeutic option, with the goal of increasing specificity and effectiveness in tumor eradication, as well as decreasing off-target or systemic toxicity. Research into further characterization and targeted therapy toward head and neck CSCs is an active and rapidly evolving field. This review discusses the current state of research into therapy against head and neck CSCs and future directions for targeted therapy.

Head and neck squamous cell carcinoma (HNSCC) remains a common and deadly disease. Historically, surgical and chemoradiation treatments have been met with modest success, and understanding of genetic drivers of HNSCC has been limited. With recent next generation sequencing studies focused on HNSCC, we are beginning to understand the genetic landscape of HNSCCs and are starting to identify and advance targeted options for patients. In this review, we describe current knowledge and recent advances in sequencing studies of HNSCC, discuss current limitations and future directions for further genomic analysis, and highlight the translational advances being undertaken to treat this important disease.