The inclusion of molecular characteristics into surgical margin analysis may not only yield a more sensitive and accurate assessment of the cells in these margins, but may also provide insight into their impacts on patients’ postoperative prognosis. This concept of the “molecular surgical margin” is advantageous, as it integrates recent advances in our understanding of head and neck carcinogenesis, while also retaining the established methodology of histopathology. This multidisciplinary approach may facilitate the development of a uniform criterion for defining the surgical margin, which will likely result in a reduced recurrence rate and improved overall patient survival.