Perineural invasion (PNI) is an ominous complication of any of the primary cutaneous malignancies. The presence of PNI has been associated with high recurrence rates, aggressive behavior and poor survival. The most common adverse outcome associated with PNI and skin cancer is recurrence. Leibovitch et.al. reported the results of the ten-year Australian Mohs database. Skin cancers with PNI were more likely to have been recurrent before coming to Mohs surgery, required more stages to clear and left a larger defect than those cancers without PNI. They were also more likely to recur after Mohs surgery. One of the most devastating outcomes of a cancer with PNI is leptomeningeal carcinomatosis (LMC) and death. The perineurium is an extension of the pia-arachnoid, and the perineural space is an extension of the leptomeninges. A cancer that gains the ability to invade the perineurium finds a path of low resistance in the perineural space, relatively protected from host defenses. The cancer is then able to spread in continuity from the bulk of the tumor along the perineural space of the peripheral nerve, eventually reaching the central nervous system. The great majority of patients with LMC have no evidence of lymph node metastases, confirming that the process of PNI is distinct from the process of metastasis. Most case reports of patients with a head and neck primary cancer that spreads via PNI into the cranial nerves and CNS suggest that this is a slow process. In some cases, patients reported many years of neurological symptoms prior to diagnosis. It is suggested that the earlier the diagnosis of PNI is made, the better the prognosis. Patients with a cutaneous SCC with “incidental asymptomatic” PNI have at least an 80% cure rate, compared to 45% cure rate for those with clinically evident PI. When the PNI extends to the skull base, the local control rate is only 25%. The Mohs surgeon typically deals with primary cutaneous malignancies at a much earlier stage of development than similar cancers of the aerodigestive tract or the deeper tissues of the head and neck. The process of PNI tends to develop early in the course of skin cancers, extends contiguously from the primary site of the cancer, and pursues an indolent natural course. All are qualities that make PNI amenable to extirpation via the Mohs technique. A stratification of PNI into “microscopic” versus “extensive” has been proposed, for the purpose of improving future outcome studies.