Aphthous ulcers are one of the most common oral diseases worldwide. Their clinical presentation is characterized by multiple, recurrent, small, round, or ovoid ulcers with circumscribed margins and erythematous haloes present in different sizes. Oral lesions similar to aphthous ulcers may be present in several systemic diseases. This article will summarize the differential diagnosis of aphthous ulceration, with emphasis on a practical guide for the management of recurrent aphthous ulceration, including topical and systemic therapy.