Syringomas are benign adnexal tumors with distinct histopathologic features, including the characteristic comma (“tadpole”) shaped tail comprised of dilated, cystic eccrine ducts. Clinically, syringomas typically present in adolescent females predominantly in the periorbital region. They may present as solitary or multiple lesions, and more rare sites of involvement include the genitals, palms, scalp, and the chest. Over the past 50 years, there have been >800 reported cases of syringoma either alone or in conjunction with a systemic syndrome, most commonly Down syndrome. The primary aim of this systematic review is to discuss the clinical features and associations of syringomas with a focus on the patient with multiple syringomas. Its secondary aims are to explore pathophysiology with a focus on multiple syringomas and provide comprehensive data on both traditional and novel treatments. Importantly, multiple syringomas present across a broad clinical spectrum. Though noted in many textbooks to be related to tumor syndromes, the association of syringomas with inherited tumor syndromes is only rarely reported in the literature. Despite multiple reported cases of syringoma, the pathophysiology remains poorly understood and treatment continues to pose a significant challenge.