Spleen-derived immune cells are considered to play central role in the progression of ischemic brain damage contributing to both the local and systemic inflammatory response initiated by an ischemic insult in the brain tissue. Brain-spleen communication in acute ischemic brain injury has been studied especially in rodent models of stroke, which mimic the acute focal brain ischemia in humans. Rodent spleens decrease in size after experimentally induced stroke, due mainly by the release of spleen`s immune-cells into the circulation. Splenectomy prior to middle cerebral artery occlusion is protective to the ischemic brain resulting in decreased infarct volume and reduced neuroinflammation. Various therapeutic strategies in clinical use aiming to protect the neural tissue after stroke were found to involve the modulation of splenic activity, altogether indicating that the spleen might be a potential target for therapy in ischemic brain injury. Importantly, the most clinical studies demonstrated that the splenic response in stroke patients is similar to the changes seen in rodent models. Thus, despite the limitations to extrapolate the results of animal experiments to humans, rodent models of stroke represent an important tool for the study and understanding of brain-spleen communication in the pathogenesis of acute brain ischemia.