Topical antineoplastic agents have a well-established role in the treatment of several dermatological conditions. Their use in the treatment of mucosal skin disease also has gained increasing recognition. Topical 5-fluorouracil (5-FU), an antimetabolite, and imiquimod, an immunomodulatory agent with antitumor properties, are the two principal topical antineoplastic agents used in the treatment of mucocutaneous diseases. Although the vast majority of their mucosal uses are currently not approved by the Federal Drug Administration, there are numerous case series, open-label studies and randomized controlled trials supporting their uses in the treatment of mucocutaneous diseases. Both topical 5-FU and imiquimod have been successfully utilized in the treatment of a wide range of mucosal diseases, including actinic cheilitis, Bowen's disease of the anal and vulvar mucosa, and genital and perianal condyloma. Reports of their uses in the treatment of mucocutaneous diseases indicate that these agents can be safely administered, though adverse effects such as local inflammation may be augmented when these agents are applied to mucosal surfaces. Additionally, locally acting intralesional chemotherapeutic agents, such as bleomycin and interferon, have well-defined applications in the treatment of mucosal skin diseases such as condyloma acuminata. As further studies are conducted, these topical and intralesional neoplastic agents, in addition to emerging agents that are in various stages of development, such as Tolllike receptor 9 agonists and ingenol mebutate, may play an increasingly important role in the future treatment of mucocutaneous diseases.