The behavior of canine mast cell tumors is heterogeneous, associated with a variety of clinical and molecular prognostic factors. The contribution of genetic aberrations has long been recognized in the form of activating KIT gene mutations and altered expression of cellular markers of proliferation. More recently, increased efforts charting the genomic landscape of mast cell tumors have provided fundamental insights into both germline and somatic aberrations associated with this disease. Accumulating evidence highlights themes of structural complexity characterized by recurrent mutations and large structural aberrations, that often parallel the presence of KIT mutations and other clinically relevant prognostic features. These genomic findings provide a blueprint for future investigation, however mechanistic studies are warranted to characterize the functional relevance of mutations and optimize clinical translation of these novel genomic studies. The purpose of this seminar is to examine the spectrum of genetic alterations associated with canine mast cell tumors, discuss current limitations in our understanding of canine mast cell tumor genetics, and explore future directions for application of this knowledge.