Although surgery remains the mainstay for the treatment of primary gastrointestinal stromal tumors (GIST), a significant number of patients experience disease recurrence within 5 years of surgery. The emergence of imatinib therapy for the treatment of patients with advanced GIST has offered unprecedented improvements in clinical outcomes for these patients. Prospective clinical trials have supported the efficacy and safety of imatinib before and after surgical resection of GIST. The American College of Surgeons Oncology Group Z9001 pivotal trial revealed that 1 year of adjuvant imatinib therapy provides significantly superior recurrence-free survival in patients with GIST after surgical resection, when compared to placebo. Additional trials and case studies have also begun to define the potential clinical benefit of imatinib in the neoadjuvant setting. Optimized risk stratification paradigms will be required to ensure the appropriate selection of patients to undergo treatment with imatinib in these settings. Risk stratification schemes are evolving that potentially will include mutation status and tumor rupture, and predictive nomograms have recently been proposed. The recent European Society of Medical Oncology and National Comprehensive Cancer Network guidelines mention use of adjuvant imatinib for ≥1 year in patients with KIT+, resectable GIST at high risk of recurrence. Moreover, the guidelines support the use of neoadjuvant imatinib in cases of limited disease if it would facilitate less extensive surgery and organ sparing. This article reviews pivotal efficacy and safety data for adjuvant imatinib and explores the potential clinical benefit of neoadjuvant imatinib in patients with GIST.