Making the most appropriate choices for diagnosis and treatment of canine and feline mast cell tumors remains challenging. An understanding of the heterogeneity of the disease process, the associated paraneoplastic disorders, and the known prognostic indicators can be helpful in making rational decisions regarding each individual case. A multimodality approach may be needed for optimal care of some patients, but the effectiveness of current medical treatment strategies continues to limit our ability to cure disseminated forms of disease.