As the dental profession moves toward additional emphasis in detection of disease and sophistication in diagnosis, biopsy is being used with increasing frequency as a diagnostic tool. This article states and elucidates simple ground rules that govern the rationale of surgical sampling of pathologic tissue. The three most common deficiencies that hamper interpretation (tissue artifact, inadequate clinical information, and inappropriate tissue sampling) are discussed, and the biopsy approach to various types of clinical lesions is reviewed.