Targeted drugs has improved the overall survival of patients with gastrointestinal stromal tumor (GIST). However, there are some difficulties and controversies. Imatinib adjuvant therapy improves recurrence-free survival, but the treatment duration has not been determined. Furthermore, whether adjuvant therapy is beneficial to the GIST with c-kit exon 9 mutation and wild type is unclear. There are currently no prospective randomized controlled trials on the role of combination of surgery with tyrosine kinase inhibitor in patients with metastatic GIST. In addition, many challenging issues remain to be solved including patients education, side effect monitoring during sunitinib treatment, the influence of difference between the Eastern patients and the Western counterparts on sunitinib treatment schedule, and the choice of regimen after imatinib and sunitinib failure, etc. Difficulties exist in the discovery of new targets in the downstream of kit gene and the concurrent use of multiple targeted drugs. This article analyzes these problems in order to achieve a consensus and discuss future directions.