The publication of the positive results of the National Institute of Neurological Disorders and Stroke (NINDS) trial of alteplase (a recombinant tissue plasminogen activator; rt-PA) for acute stroke patients in 1995 and its approval by the US Food and Drug Administration as well as the American Academy of Neurology and American Heart Association increased the interest and attention of the medical community in acute stroke treatment. However, the implication of this NINDS Stroke Study and other thrombolytic trials in clinical practice remains controversial and debated. Furthermore, the recent publication of the results from the European Cooperative Acute Stroke Study II (ECASS II) and Alteplase Thrombolysis of Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) studies will feed the controversy, since the results of these two studies are disappointing and do not confirm the positive results of the NINDS Stroke Study as expected by clinicians managing patients with acute stroke. The Standard Treatment with Alteplase to Reverse Stroke (STARS) and Cleveland studies, which involved a large number of community hospitals to assess the safety profile and the benefit of rt-PA thrombolysis for acute stroke patients in clinical practice, have shown controversial results. Consequently, the issue arises of which is the more reasonable position concerning thrombolysis by alteplase, which seems to work but has not been proven yet beyond reasonable doubt? The recent publication of the results from the Prolyse in Acute Cerebral Thromboembolism (PROACT II) study has shown that intra-arterial thrombolysis with prourokinase is a benefit treatment in stroke patients with a proven middle cerebral artery occlusion within 6 h of stroke onset. Numerous trials devoted to neuroprotection against acute ischemic stroke have been prematurely stopped because of safety concerns or poor risk-benefit ratios, but some new neuroprotective drugs seem promising and are being tested in ongoing studies. The third issue under study concerns the use of antithrombotic drugs in the acute phase of stroke, particularly the new potent platelet glycoprotein IIb/IIIa antagonists such as abciximab. In this paper, we have reviewed selected recent clinical trials focusing on recent advances in acute stroke therapy.