Pigmented entities are relatively common in the oral mucosa and arise from intrinsic and extrinsic sources. Conditions such as melanotic macules, nevi, smoker's melanosis, amalgam and graphite tattoos, racial pigmentation, and vascular blood-related pigments occur with some frequency. Addison disease, Peutz-Jeghers syndrome, and Laugier-Hunziker syndrome also appear in perioral and oral locations as pigmented macules. Detailed knowledge of melanoma at the molecular level allows the development of new treatment alternatives and to design effective new drugs. Addison disease presents as adrenal cortical hypofunction along with splotchy or generalized bronzing of the mucosa and skin. Peutz-Jeghers syndrome has periorificial freckling along with hamartomatous intestinal polyps, and, as a differential diagnosis, Laugier-Hunziker syndrome presents with macular mucocutaneous hyperpigmentation and melanonychia with no known systemic disease association. We conducted this review using a comprehensive search of MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from January 1, 1970, through February 28, 2017.