This systematic review aims at assessment of the available evidence for systemic therapy options for patients with advanced gastrointestinal stromal tumors beyond first-line imatinib. Eligible trials were identified using databases search. In total, 26 studies were eligible and included in the final analysis. Among second-line studies, median progression-free survival ranged from 1.9 to 10 months while median overall survival ranged from 15 to 62 months. Among third-line agents, median progression-free survival ranged from 1.8 to 4.6 months while median overall survival ranged from 8.2 to 19 months. The available data for the second-line suggest that sunitinib is the best option while in the third line, regorafenib is the best option.