Gastrointestinal stromal tumors (GISTs) are rare malignancies, and historically had a poor prognosis, with little benefit from traditional anticancer therapies. The management of GISTs has undergone a paradigm change in recent years with the detection of activating mutations in the majority of these tumors. This knowledge has led to the development of targeted treatments which have dramatically improved benefit rates and survival. The tyrosine kinase inhibitor, imatinib, has become the standard of care for both those with high-risk resected GIST, and as first-line therapy in metastatic GIST. However, some patients demonstrate innate resistance to imatinib or, for many, resistance develops despite an initial response. Other tyrosine kinase inhibitors with a broader spectrum of action, such as sunitinib and sorafenib, have been investigated and show some benefit after the use of imatinib. Regorafenib, an orally available multitargeted tyrosine kinase inhibitor with antiangiogenic activity, has also demonstrated preclinical evidence of activity against a number of solid tumors and further studies have proven it to be effective in GISTs following failure of standard therapy, with manageable toxicity profile. It has now received licensing approval in a number of countries both for the treatment of GISTs and for colorectal cancer, and further research is ongoing. With a number of potential agents now available to treat this disease, clinicians must now consider questions of timing and sequencing to maximize the benefit from these treatments, and the role that new agents such as regorafenib could play in further advancing changes.