In the mid-1930s working as a cancer research assistant during medical school, Frederick Mohs observed that injection of 20% solution of zinc chloride induced in situ tissue fixation, preserving the cells for microscopic examination. From this finding, Mohs developed a process of fixing tissue using zinc chloride in vivo and excising tumor in horizontal layers under microscopic control till complete clearance had been achieved. The new technique, called chemosurgery, was first reported by Mohs in 1941. The main complication of chemosurgery was the use of zinc chloride as the in vivo tumor fixative which caused significant pain and tissue irritation. From 1953, zinc chloride fixation was substituted by the production of fresh frozen tissue sections for the microscopic examination. This allowed multiple stages to be completed in a single day and averted tissue irritation to permit immediate repair of the wound. Subsequently the technique was renamed MMS and has become the treatment of choice in high risk, large, contiguous skin tumors especially over critical anatomical sites of the head and neck. Conventional surgery involves excision of a tumor with a preselected wide margin of normal skin and then processing of the pathology specimen in vertical sections at 2–4 mm intervals, akin to a ‘bread loaf’ series of sections through the tumor. As only 1–2% of the tumor margin is examined, false negative clearance of tumors may be reported. MMS is a specialized type of cutaneous surgery utilizing staged excision of the tumor with a minimal margin of normal skin and intraoperative microscopic examination of the entire excised peripheral and deep histological margin by horizontal frozen sections to ensure complete tumor extirpation. If residual tumor is present, the involved margin is precisely mapped onto the patient and re-excised in further stages till complete clearance is achieved. Thereby, MMS offers a higher cure rate than standard surgery for skin cancer treatment, reducing the morbidity and mortality from future recurrence, and simultaneously allowing maximal conservation of adjacent healthy skin. This is especially important when managing reconstructions in the cosmetically and functionally sensitive sites of the head and neck region.