With the introduction of depth of invasion to the AJCC 8th edition of TNM staging in head and neck, assessment of tumor depth in oral cavity cancer is increasingly important for both general and head and neck oncology practitioners. An important component of adequate oral cavity tumor resection, especially in cases of deeply infiltrative tumors, is a sufficient tumor-free margin around the lesion. In this Expert Series, we will provide a practical guide for approaching and assessing margins both pre- and intra-operatively, with advice and suggestions that will be widely applicable to otolaryngologists. We will describe methods for pre-operative DOI assessment, review prior studies related to margins from the specimen versus the wound bed, discuss the definition of an adequate margin (close vs negative), present methods for intraoperative margin assessment using ultrasound and other forms of imaging, and provide a glimpse of what the future hold for molecular-based margin assessment as well. We will also discuss the post-operative management of close and positive margins in oral cavity head and neck squamous cell carcinoma, with a specific focus on NCCN and evidence-based guidelines for adjuvant radiation and chemotherapy. Importantly, our discussion will be particularly focused on early-stage oral cavity lesions, which are often addressed by the general otolaryngologist, to provide a more practice relevant set of tools and tips. This important topic will be approached through case-based discussion including live polling of the audience to help shed insight into state-of-the-art practice patterns while incorporating input of experts in head and neck oncology.