This article discusses the orofacial clinicoradiographic features of systemic diseases that manifest in the orofacial region. The systemic diseases discussed are grouped into the following: autoimmune diseases, endocrine diseases, bone diseases, hematologic diseases, syndromes, and malignancies. The radiographic manifestation ranges from radiolucent bony destruction, increased bone density, calcification, thinning of cortical plate, loss of trabeculation, missing teeth, and supernumerary teeth. It is imperative for clinicians to be cognizant of these findings, as they may be the first manifestation of these systemic diseases.