Amyotrophic lateral sclerosis (ALS) is a devastating disease which affects both motor neurons and skeletal muscle. Skeletal muscle atrophy and weakness are two of the main features of ALS disease progression. We hypothesized that disruptions in the sarcoplasmic reticulum and endoplasmic reticulum (SR/ER) play an important role in skeletal muscle pathology in ALS. This dissertation is comprised of three studies investigating ER stress in skeletal muscle and its relationship to oxidative stress and SR Ca2+ regulation. Study#1 established that the ER stress markers PERK, IRE1α and Grp78/BiP as well as the ER-stress specific apoptotic marker CHOP are upregulated in skeletal muscle of ALS transgenic (ALS-Tg) mice and that these changes were greater in fast white vs. slow red muscles. Study #2 showed that skeletal muscle-specific overexpression of the SR Ca2+ ATPase SERCA1 improved motor function, delayed disease onset and attenuated the muscle atrophy in ALS-Tg mice but did not attenuate the ER stress markers. Study #3 investigated the potential molecular mechanisms of ER stress in skeletal muscle pathology in ALS. This final dissertation study showed that the Grp78/BiP protein interacts with SERCA1 and various mitochondrial proteins including ATP synthase subunits in skeletal muscle of ALS-Tg but not wild-type mice. Disruption of the Grp78/BiP-SERCA1 protein-protein interaction by antibody sequestration of Grp78/BiP decreased SERCA ATPase activity, suggesting that Grp78/BiP preserves SERCA function. In C2C12 myocytes, oxidative stress induced by H2O2 dramatically decreased SERCA ATPase activity and catalase, which removes H2O2, could recover SERCA ATPase activity. Inhibition of ER stress by 4-PBA partially rescued H2O2-induced decreases in SERCA ATPase activity suggesting that this mechanisms can mitigate oxidative stress-induced SERCA impairment. Collectively, these studies provided insight into the cellular mechanisms underlying skeletal muscle dysfunction in ALS and suggest a role for ER stress chaperone proteins in minimizing Ca2+ overload damage in skeletal muscle. These data further suggest that the ER stress pathway could be a novel therapeutic strategy to treat skeletal muscle dysfunction in ALS.