Liquid biopsies (LB) are emerging in the oncology field, with promising data as new diagnostic, prognostic and treatment-monitoring tools. Squamous cell carcinoma of the head and neck (SCCHN) is a heterogenous disease and many challenges remain to improve patient outcomes. Liquid biopsy could be of interest at different stages of SCCHN disease, including better screening to diagnose more patients at an early stage, early detection of relapse after curative treatment, and the implementation of precision medicine. As LB is very attractive by the ease of sampling, this field is moving fast. Therefore, it is important to be aware of the potential applications but also the limitations of these new tools in regards to technical aspects and interpretation of the data. In this review, we will first give an overview of potential clinical applications and technical challenges of circulating tumor DNA (ctDNA) and then focus on current available data of ctDNA in SCCHN. Although the literature on ctDNA analysis for SCCHN is scarce compared to other tumors, preliminary results seem to hold promise for the future, including the detection of minimal residual disease or the detection of potentially targetable events through liquid biopsy. Prospective liquid-biopsy driven clinical trials are needed to validate its clinical relevanc