Ischemic brain injury can be anticipated in a number of clinical settings such as procedures associated with a high-risk for stroke, patients with transient ischemic attacks or minor strokes who are at substantial risk for early recurrence and patients with multiple vascular risk factors with an enhanced risk for ischemic stroke over many years. In such high-risk settings, it may be possible to employ neuroprotective drugs prophylactically to reduce the extent and clinical consequences of ischemic events. The concept of prophylactic neuroprotection can be envisioned for varying time periods and with a variety of drug classes depending upon the target population. This review will focus on which target populations should be considered for prophylactic neuroprotection trials and which drugs might be used in such trials.