Abstract: Understanding mechanism of imatinib resistance in gastrointestinal stromal tumors (GIST) and developing new therapeutic targets and schemes to address this resistance exhibit great potential to improve the long-term prognosis of patients with GIST. This review summarizes exiting research into the molecular characteristics of GIST and mechanisms of imatinib resistance acting via non-coding RNA, lysosomes, key protein molecules, fibroblast growth factor-2 (FGF-2), and other modulators. Research shows that different drug resistance mechanism networks are closely connected and interrelated. Combining imatinib therapy with multiple drugs that inhibit the resistance mechanism shall present new options treating GIST thereby improving prognosis. Identification and implementation of individualized treatment strategies based on drug resistance mechanisms will provide new adjuvant treatment options for patients with GIST resistant to imatinib, thus delaying progression of GIST.