Gorlin Syndrome represents a strong historical intersection between Plastic and Reconstructive Surgery and Medical Genetics. Dr Robert J. Gorlin and Dr Robert W. Goltz first identified this syndrome in 1960, characterised by early-onset basal cell carcinomas, odontogenic keratocysts,skeletal bifid ribs and falx cerebri calcifications. The characterisation of seemingly discondordant signs into a single entity was ground-breaking at the time. The PTCH1 gene-mutation, identified in the 1990s, is the primary cause of Gorlin Syndrome. This Hedgehog-signalling pathway gene is essential in embryonic development and cell-growth regulation. Refined understandings of PTCH1 mutations allowed for correlation between developmental biology and cancer predisposition. This transformed Gorlin Syndrome from a condition diagnosed solely on physical signs to a model for studying gene-phenotype interactions with significant impacts on the Plastic and Reconstructive Surgeon. Multiple surgical resections, complex defect reconstruction and a high-prevailing risk of recurrence introduce significant surgical challenges. Neoadjuvant/adjuvant Hedgehog-pathway inhibitors, including vismodegib and sonidegib, are novel treatment avenues. Though limited by a scarcity in large-volume, high-quality trials, preliminary evidence suggests reduction in tumour size, recurrence rate and subsequent surgical burden. These may be more viable, less-invasive options for an already high-risk population. Gorlin Syndrome is a key chapter in oncosurgical history, with an interplay between Plastic and Reconstructive and Medical Genetic services. Developments in Molecular Biology continue to impact additional treatment options for Gorlin Syndrome.