The effects of exercise pre-conditioning on lessening the impact of ischemia/reperfusion injury provide pivotal information and potential targets for future pharmacological intervention. Exercise induces increased expression of neurotrophic factors, the extracellular matrix (ECM) proteins, integrins, angiogenic factors, as well as tumor necrosis factor (TNF-α) and heat shock proteins (Hsp-70). These factors all directly enhance the neurovascular unit and alleviate the harmful effects following ischemia/reperfusion injury. Furthermore, pre-conditioning decreases expression of matrix metalloproteinase (MMP-9) and Toll-like receptor-4, which ameliorates the inflammatory response and apoptosis following ischemic insult. Perhaps most importantly, exercise pre-conditioning shows a propensity to simultaneously favor cell survival mechanisms and inhibit apoptotic pathways via interactions between TNF-α and Hsp-70, which are regulated by extracellular signal-regulated kinases-1 and -2 (ERK1/2). Finally, chronic exercise preconditioning increases cerebral metabolism, effectively enhancing the neuronal response to increase ATP production following periods of hypoxia. The purpose of this review is to demonstrate the various effects of exercise pre-conditioning on the neural response to ischemia/reperfusion injury as a means of demonstrating potential targets for prevention and treatment of acute ischemic events.