This Special Issue of Current Issues in Molecular Biology explored the current knowledge and innovative concepts regarding preclinical and clinical research into stroke mechanisms, prevention, and treatment and provided a critical overview of the underlying factors involved in stroke-related brain injury, especially the role of cell signaling in excitotoxicity, inflammation, apoptosis, and the newly described types of cell death such as ferroptosis and their potential treatment. Gene and protein expression profiles after stroke and neurogenesis, angiogenesis, and neuroplasticity are other important features in stroke and should lead to the better understanding of the pathophysiology of acute stroke.