The ability of pharmacological agents to limit secondary biochemical damage and cell death has been well established in numerous animal models of stroke, head injury, and spinal cord injury, yet the results of such neuroprotective treatment strategies in human injury have been disappointing. A number of conceptual and methodological issues have undoubtedly contributed to the difficulties in translating the experimental results to the clinic. Most recently, different experimental approaches and altered clinical trial methodologies have provided renewed, albeit cautious, optimism regarding future clinical trials of neuroprotective agents. Herein, we reviewed both the critical problems and potential solutions, emphasizing recent experimental and clinical work.