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The approval of imatinib for the treatment of patients with gastrointestinal stromal tumor has (GIST) revolutionized the treatment in the adjuvant setting and metastatic disease. Imatinib is an inhibitor of the receptor tyrosine kinases KIT and platelet-derived growth factor receptor (PDGFR), which are constitutively activated in most cases of GIST. Even though substantial survival improvements have been observed with imatinib, primary or secondary resistance to imatinib represents a major challenge in the treatment of GIST. This short review focusses on treatment strategies to overcome resistance and provides an overview of promising new agents currently evaluated for imatinib-refractory disease.