Extensive efforts have recently been devoted to developing noninvasive imaging tools capable of delineating brain tissue viability (penumbra) during acute ischemic stroke. These efforts could have profound clinical implications for identifying patients who may benefit from tPA beyond the currently approved therapeutic time window and/or patients undergoing neuroendovascular treatments. To date, the DWI/PWI MRI and perfusion CT have received the most attention for identifying ischemic penumbra. However, their routine use in clinical settings remains limited. Preclinical and clinical PET studies with [¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) have consistently revealed a decreased¹⁸F-FDG uptake in regions of presumed ischemic core. More importantly, an elevated¹⁸F-FDG uptake in the peri-ischemic regions has been reported, potentially reflecting viable tissues. To this end, this paper provides a comprehensive review of the literature on the utilization of¹⁴C-2-DG and¹⁸F-FDG-PET in experimental as well as human stroke studies. Possible cellular mechanisms and physiological underpinnings attributed to the reported temporal and spatial uptake patterns of¹⁸F-FDG are addressed. Given the wide availability of¹⁸F-FDG in routine clinical settings,¹⁸F-FDG PET may serve as an alternative, non-invasive tool to MRI and CT for the management of acute stroke patients.