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Stroke is one of the leading causes of death and serious disability in Westernized societies. The risk of stroke approximately doubles with each decade after the age of 55. Therefore, even though the incidence of stroke is declining, mostly because of the efforts to lower blood pressure and reduce smoking, the overall number of strokes is increasing due to the aging of the population.While stroke prevention by healthy lifestyle is effective in decreasing the risk of stroke, post stroke pharmacological strategies aimed at minimizing stroke-induced brain damage and promoting recovery are highly needed. Unfortunately, several candidate drugs that have shown significant neuroprotective efficacy in experimental models have failed in clinical trials and no treatment for stroke based on pharmacological neuroprotection is available today.Glucagon-like peptide 1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i) are clinically used against type 2 diabetes. Interestingly, these drugs have also shown promising effects in decreasing stroke incidence and increasing neuroprotection in clinical and preclinical studies, respectively. However, the mode of action of these drugs in the brain is largely unknown. Moreover, while it was previously thought that GLP-1R agonists and DPP-4i act via similar mechanisms of action, recent data argue against this hypothesis.Herein, we review this promising research area and highlight the main questions in the field whose answers could reveal important aiming to developing effective anti-stroke therapies.This article is part of the Special Issue entitled ‘Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.’GLP-1R agonists and DPP-4 inhibitors are clinically used against type 2 diabetes.Preclinical studies show that these drugs can also exert anti-stroke efficacy.The neuroprotective mechanisms of GLP-1R agonists and DPP-4 inhibitors differ.Mechanistic studies are needed to fully understand the neuroprotective efficacy.Further clinical studies are needed to understand their potential use against stroke.