The oral multikinase inhibitor regorafenib targets both tumor cell proliferation and vasculature and is active in heavily pretreated patients with metastatic colorectal cancer, for which the US FDA granted its approval in September 2012. The benefit for regorafenib was seen in these patients in most prespecified subgroups. The drug is also being used in other tumor types where it has shown exciting potential especially in gastrointestinal stromal tumors. The drug is well tolerated but requires close monitoring during administration. Common side effects include asthenia/tiredness, loss of appetite, hand–foot skin syndrome, diarrhea, mucositis, weight loss, infections, hypertension and rash. Serious adverse events to look out for are liver toxicity, hemorrhage and gastrointestinal perforation. Biomarker data should help us to optimize the use of these drugs to select which patients are most likely to benefit.