The democratization of Next Generation Sequencing (NGS) in routine patient care raised several questions related to the accurate interpretation and the classification/priorization of molecular alterations identified in terms of actionability. Several guidelines have been proposed to prioritize actionable molecular alterations (MA) according to their levels of clinical evidence when matched to molecularly targeted agents, one being the European Society for Medical Oncology (ESMO) Scale of Actionability of Molecular Targets (ESCAT). ESCAT ranks MA on six levels of evidence defined as tiers on the basis of their clinical actionability (tier I, tier II, tier III, tier IV, tier V, and tier X). The impact of ESCAT on head and neck cancer (HNC) management in general is still to be demonstrated particularly in rare HNCs such as adenoid cystic carcinoma (ACC). More than 30 genes are considered to be actionable in head and neck squamous cell carcinoma (HNSCC), yet a limited number are classified as Tiers I/II with a higher level of clinical evidence. In ACC around 40% of MA are targetable by tyrosine kinase inhibitors, yet clinical evidence remains to be demonstrated. Primary indication for using ESCAT classification in HN cancers is for patients who undergo genomic profiling via Molecular Tumor Boards (MTBs). In this context, HN cancer patient enrollment in clinical trials using drugs matched to MA should be encouraged.