While surgery remains the mainstay of treatment for canine and feline mast cell tumors (MCTs), there are circumstances where systemic therapy is indicated. These include locally advanced/disseminated tumors, situations where aggressive local therapy is declined, and adjuvant therapy for tumors at high risk of eventual metastasis. A large number of both traditional cytotoxic and targeted agents have been evaluated for the medical treatment of MCTs; however, there is very little information available regarding efficacy of most treatments when employed postoperatively to delay/prevent local recurrence or metastasis. This lecture will review the data regarding conventional cytotoxic therapies, kinase inhibitors and “frontier” therapies (e.g., monoclonal antibodies, protein kinase C activators) for measurable MCTs in dogs and cats. Combinatorial therapies (e.g., kinase inhibitor/chemotherapy, kinase inhibitor/radiation therapy combinations) will be reviewed. The (limited) information evaluating postoperative therapy will be discussed, and the available data regarding the utility of specialized testing for treatment allocation (e.g., c-kit gene mutation testing, KIT protein localization) will be discussed.