The purpose of this dissertation was to investigate the molecular events associated with the onset of skeletal muscle disuse in humans. Study I examined global gene expression changes in vastus lateralis muscle following 48h unloading (UL) and 24h reloading (RL) in humans. Results showed that functions related to protein degradation and oxidative stress were enriched following UL and that these global gene expression patterns were not readily reversed following RL, thus indicating that molecular events associated with short-term disuse may persist beyond the duration of the stimulus. In contrast to previous work in IM, collagen gene expression increased in this study, demonstrating that differences in molecular signaling may exist among disuse models in humans. Study II of this dissertation expanded on the findings of Study I to investigate global gene expression patterns related to the early stage of multiple disuse models. Microarray data collected 48h post-UL in Study I were analyzed within the context of data previously collected in our laboratory following 48h immobilization (IM) and spinal cord injury (SCI). Results showed that the disuse models shared a small subset of commonly differentiated genes. Furthermore, the similarities between IM, SCI, and UL extended beyond specific genes to include commonly enriched functions and pathways such as protein degradation and oxidative stress, suggesting that these molecular mechanisms are involved in the early stages of disuse, regardless of specific stimulus. In Study III, an in vitro model of skeletal muscle was used to test the exploratory hypothesis that induction of oxidative stress response gene heme oxygenase-1 (HMOX1) would lead to decreases in gene expression associated with proteolysis, namely ubiquitin E3 ligases atrogin1 and MuRF1, as well as increased XXT cleavage (a marker of metabolic enzyme activity). In this study, C2C12 myotubes were pre-treated with hemin (an inducer of HMOX1) and then treated with H2O2 to elicit oxidative stress. Results showed that hemin treatment resulted in increased HMOX1 expression and decreased E3 ligase expression. Furthermore, hemin-treated cells exhibited increased XTT cleavage compared to controls. HMOX1 may be a promising gene target to protect against oxidative stress that accompanies early stages of disuse.