Stroke is associated with a high risk of disability and mortality, and with the exception of recombinant tissue-type plasminogen activator for acute stroke, most treatments have proven ineffective. Clinical translation of promising experimental therapeutics is limited by inadequate stroke models and a lack of understanding of the mechanisms underlying acute stroke and how they affect outcome. Bidirectional communication between the ischemic brain and peripheral immune system modulates stroke progression and tissue repair, while epidemiological studies have provided evidence of an association between organ dysfunction and stroke risk. This crosstalk can determine the fate of stroke patients and must be taken into consideration when investigating the pathophysiological mechanisms and therapeutic options for stroke. This review summarizes the current evidence for interactions between the brain and other organs in stroke pathophysiology in basic and clinic studies, and discusses the role of these interactions in the progression and outcome of stroke and how they can direct the development of more effective treatment strategies. (C) 2015 Elsevier Inc. All rights reserved.