Small-molecule tyrosine kinase inhibitors (TKIs) have revolutionized the targeted treatment of various cancers, including gastrointestinal stromal tumors (GISTs). Recent evidence suggests the possibility of cardiotoxicity secondary to TKI treatment of GISTs. Preclinical studies indicate that imatinib and sunitinib may be directly toxic to cardiac myocytes. Clinically, cardiotoxicity attributable to imatinib seems to be infrequent and manageable, whereas that attributable to sunitinib is more common and more severe. Further prospective studies with objective cardiac monitoring and long-term follow up are needed to define more accurately the incidence, natural history, and risk factors for developing cardiotoxicity associated with TKIs used in the treatment of patients who have GISTs. In this review, the authors discuss what is known regarding the cardiovascular effects of TKIs used in the treatment of GISTs.