The concept of surgical margins was born a long time ago but still lacks a univocal and sound understanding. The current biological rationale behind the recommendations on margins management relies on two pillars: (1) the observation that groups of cancer cells can leave the macroscopic tumor and disseminate throughout adjacent tissues with different degrees of aggressiveness; (2) the belief that removal of all (or most of) cancer cells can cure the patient. However, this background is undermined by some pieces of evidence. For instance, it has been proven that tissues surrounding cancer often bear precancerous traits, which means that cutting through non-cancerous tissues does not equate to cut through healthy tissues. The head and neck exquisitely poses a number of challenges in the achievement of negative margins, with special reference to anatomical complexity, high density in relevant structures, and unique histological heterogeneity of cancers. Currently, intraoperative margins evaluation relies on surgeons’ sight, palpation, ability to map tumor extension on imaging, and knowledge of anatomy, with some optical imaging technologies aiding the delineation of the mucosal margins of excision. Frozen sections are currently used to intraoperatively evaluate margins, yet with debate on whether and how this practice should be performed. Future perspectives on improvement of margins control are threefold: research is oriented towards refinements of understanding of cancers local progression, implementation of technologies to intraoperatively render tumor extension, and employment of optical imaging modalities capable of detecting foci of residual tumor in the surgical bed.