The histopathologic status of excisional margins of malignant neoplasms has long been used as a potential indicator for recurrences and prognosis. The predictive ability of the margin, however, is far from satisfactory. Perhaps nowhere else in oncologic pathology has the significance of these margins been as intensively studied as in squamous cell carcinomas of the upper aerodigestive tracts. This review is, in part, a critique of current applications and the clinical implications of surgical margins for the removal of squamous cell carcinomas in these tracts. Specific points addressed in this article are: 1) postremoval (artifactual) changes in measurements; 2) the impact of margin status, as currently assessed, on recurrence and patient outcome; 3) margins and conservation surgery of the larynx; 4) margins and bone (mandible) invasion; and 5) molecular (p53 and eIF4E) margins.