The persistence of cancerous cells after surgery in oral squamous cell carcinoma (OSCC) represents a major challenge, as it often leads to local recurrences and secondary primary tumors, which are eventually responsible for a large proportion of deaths. This persistence is currently evaluated by histological analyses. In this review we discuss some important pitfalls of the histopathological analysis, such as margin evaluation, specimen shrinkage and T staging. In addition, we critically analyze the appropriateness of current surgical techniques in relation to the concept of field cancerization. Finally, we describe some novel imaging and molecular approaches, which might be useful in tailoring surgical resections and encourage the use of OSCC animal models to explore and provide proof of concept of the feasibility and potential clinical utility of innovative surgical protocols.