Abstract: | Head and neck squamous cell carcinomas are aggressive tumors that often present at advanced stage in difficult‐to‐biopsy regions of the head and neck. With the rapid move to analyze circulating tumor DNA (ctDNA) to either detect cancer or monitor disease progression and response to therapy, we have designed this article as a primer to understand the recent studies that support a transition to use these circulating biomarkers as a part of routine clinical care. Whereas some technical challenges still need to be overcome, the utility of ctDNA in cancer care is already evident from these early studies. Therefore, it is critical to understand recent advances in this area as well as emerging questions that need to be addressed as these biomarkers move closer to enhancing routine clinical care paradigms. Laryngoscope, 129:1836–1843, 2019 |