Proper management of an oral mucosal lesion begins with diagnosis, and the gold standard for diagnosing disease, oral or otherwise, is tissue biopsy. The oral environment, which is moist and confined, poses challenges for collecting a viable tissue sample that will be suitable for diagnosis. These challenges are further compounded by the myriad of biopsy techniques and devices now available. In addition, certain oral subsites are subject to diagnostic pitfalls that necessitate modifications of technique. This article provides an overview of the oral soft-tissue biopsy and highlights some potential pitfalls.