Mohs micrographic surgery is often considered the treatment of choice for a variety of skin malignancies. In recent years, the application of immunostaining techniques has facilitated the successful removal of a number of common and less common cutaneous malignancies, including basal cell carcinoma, squamous cell carcinoma, malignant melanoma, dermatofibrosarcoma protuberans, microcystic adnexal carcinoma, sebaceous carcinoma, atypical fibroxanthoma, extramammary Paget's disease, and even sarcomas. Immunostains highlight the tumor cells and allow the Mohs surgeons to pinpoint and eliminate the residual tumor at the surgical margin. It is especially helpful when a tumor presents with subtle or nonspecific histologic features or when a tumor is masked in a pocket of dense inflammation. However, the cost, the labor, and the time consumption are of concern to many of our peers, as are the diversity of antigens, which may overwhelm some. This article serves as a review of the literature on current uses of immunostaining in Mohs micrographic surgery and as a summary of their realistic applications in the dermatologic surgeon's practice. We conclude that immunohistochemical technique has played an important role in Mohs surgery advancement. With greater use and more cost-effective staining methods, we believe that the use of immunostains in a Mohs practice will become routine.