Stroke is one of the main causes of neurological disability worldwide and the second cause of death in people over 65 years old, resulting in great economic and social burden. Ischemic stroke accounts for 85% of total cases, and the approved therapies are based on re-establishment of blood flow, and do not directly target brain parenchyma. Thus, novel therapies are urgently needed. In this review, limb remote ischemic conditioning (RIC) is revised and discussed as a potential therapy against ischemic stroke. The review targets both (i) fundamental research based on experimental models and (ii) clinical research based on clinical trials and human interventional studies with healthy volunteers. Moreover, it also presents two approaches concerning RIC mechanisms in stroke: (i) description of the underlying cerebral cellular and molecular mechanisms triggered by limb RIC that promote neuroprotection against stroke induced damage and (ii) the identification of signaling factors involved in inter-organ communication following RIC procedure. Limb to brain remote signaling can occur via circulating biochemical factors, immune cells, and/or stimulation of autonomic nervous system. In this review, these three hypotheses are explored in both humans and experimental models. Finally, the challenges involved in translating experimentally generated scientific knowledge to a clinical setting are also discussed.