Oral cavity squamous cell carcinoma (OCSCC) has a yearly incidence of 274,000 patients. Twenty percent to 30% of patients will harbor occult regional metastases, an important feature that correlates with worse outcomes. Supraomohyoid neck dissection (SND) is the gold standard treatment, but because of recent successes of sentinel lymph node (SLN) biopsy in the management of breast cancer and melanoma, many have begun evaluating its use in head and neck mucosal cancers. SLN biopsy offers patients decreased morbidity compared with SND, and has shown reproducibly low false-negative rates, high-negative predictive values, and high sensitivities. Limitations with floor-of-mouth primaries and delayed secondary SNDs have been described, but a new agent designed to address these shortcomings, Lymphoseek (Neoprobe Corp.; Dublin, OH), is currently under investigation. This article reviews the current literature on SLN biopsy and introduces a phase 3 study evaluating the efficacy of Lymphoseek in SLN biopsy of OCSCCs.