The overexpression of heat shock protein 70 (Hsp70) provides cytoprotection to cells, making them resistant to otherwise lethal levels of stress. In this review, the role Hsp70 plays in protecting both cardiac and skeletal muscle against the pathophysiological effects of oxidative stress are examined, with a focus on the molecular basis for the cytoprotective effects of Hsp70. The ability of Hsp70 to maintain cell survival undoubtedly involves the regulation of multiple steps within apoptotic pathways, but could also involve the regulation of key upstream mediators of apoptosis (i.e., oxidative stress, Ca2+ overload). Hsp70 can stabilize the structure and function of both the skeletal muscle and cardiac Ca2+ pump under heat stress conditions. Given that Ca2+ overload has long been implicated in cell death, Hsp70 might protect muscle cells by maintaining cellular Ca2+ homeostasis, thereby preventing the initiation of apoptosis. The functional interaction between Hsp70 and Ca2+ pumps might also promote improvements in muscle contractility after exposure to oxidative stress.