A wide variety of benign lesions and diseases are detected on the oral mucosa. Oral mucosal lesions can also be associated with an underlying systemic disease. The correct diagnosis of mucosal lesions, which may share similar clinical and demographic features, is a challenge for a dentist and general practitioner. Diagnostics of oral mucosal lesions is based on a thorough investigation of the patient and a careful anamnesis. In addition, diagnostic tests, including biopsies and microbiologic samples, are usually required for establishing a proper diagnosis. This is particularly important for early detection of premalignant lesions and oral cancer, because their prognosis is mainly dependent on the stage of the disease at the time of diagnosis. Since bacteria, fungi, and viruses are causative agents in a number of mucosal lesions and diseases, microbiologic samples are needed, if any infectious aetiology is suspected. Blood tests are often helpful for diagnosis of systemic diseases.