Recurrent Aphthous Stomatitis (RAS) is a condition in which aphthous ulcers repeatedly occur in the oral cavity. It is prevalent in developed countries, occurring in all ages, geographic regions and races and about 80% of people have one episode of oral aphthous ulcers before the age of 30 years. With no laboratory procedures to confirm the diagnosis, treatment is mainly empirical in nature and focuses on short-term symptomatic management. Although numerous treatment modalities have been recommended, only a few are evidence based and can be considered for the optimal management of RAS. Biologic agents are a new category of drugs which acts by blocking specific pathways associated with the pathophysiology of neoplastic or immune-mediated diseases. These agents have targeted immunosuppressive or anti-inflammatory actions. In patients of RAS who were not responding to standard therapy, etanercept, adalimumab, infliximab and Interferon-Alpha (INF-α) were found to be useful. The objective of this review was to propose and review a treatment protocol to be followed for the optimal management of RAS. We reviewed several evidence-based studies and through this review we recommend topical interventions as the first-line of therapy since they are associated with low risk of systemic side effects. Due to limitations in the number of evidence-based trials and the insufficient data to support or refute the efficacy of the therapies prescribed, larger evidence-based clinical studies and literature reviews are needed to further improvise the optimal methodology for the effective management of RAS.