Intravenous and intra-arterial thrombolysis (IVT and IAT, respectively) are the two major therapeutic options for management of acute ischemic stroke (AIS). However, the FDA has only approved IVT for management of AIS, when the patient presents within 0-4.5 hours of AIS onset. This recommendation was based on numerous randomized controlled trials (RCT) which, when analyzed together, showed a net benefit towards the use of IVT. But a narrow therapeutic window, which is rarely met by the individual, and the relative inefficacy of IVT in large artery occlusions, leaves a lot to be desired in the management of AIS. Thus, in these situations, the focus has shifted towards the possibility of using IAT, both pharmacologic and mechanical. Numerous studies have been performed comparing IAT and IVT in treating AIS. None of the major trials found any significant benefit of IAT when compared with IVT. In this review, we compare the efficacy and the relative benefits of both IAT and IVT and discuss the significant findings and limitations of major trials studying these therapies. We suggest that IAT appears as a promising alternative to IVT in specific cases. The lack of benefit observed in major RCTs may have been due to inadequate study designs and execution. Further randomized controlled trials are underway to better understand the role of IAT in AIS.