Smoking increases risk for musculoskeletal injury and protracts healing. The underlying mechanisms have not been explored, yet dysregulated inflammatory responses may contribute. To investigate these risks, Study 1 of this dissertation monitored typical responses to muscle damaging eccentric contractions (ECC) in smokers and nonsmokers. Smokers experienced greater muscle fatigue both during and immediately after ECC and greater delayed hyperalgesia, a phenomenon known as delayed onset muscle soreness (DOMS), than did non-smokers. DOMS (driven by inflammation) peaks 48h after ECC, when there is a shift from pro- to anti-inflammatory signaling; thus I chose to investigate this time further in smokers. The “late inflammation” time point is relatively unstudied mechanistically. Therefore, in Study 2 I further characterized the post-ECC muscle response in non-smokers and focused on hyperalgesic pathways. Transcriptome analyses revealed greater proliferation and pro-inflammatory signaling at 3h, which returned to baseline by 48h. Activity of key regulatory pathways canonical (p65) nuclear factor kappa-beta (NFκB) and extracellular regulated kinase (ERK)1/2 mimicked the pro- (activated) to anti- viii inflammatory (de-activated) shift. In addition, nerve growth factor (NGF), a hyperalgesic-modifier, was also induced. Further testing revealed suppressed 48h p65 activity. In Study 3 I tested these pathways, and non-canonical NFκB (REL-B) signaling (specifies oxidative muscle fibers), in skeletal muscle from smokers and non-smokers 48h post-ECC. Smokers had fewer oxidative (Type I) muscle fibers. Further, REL-B, enhanced in non-smokers at 48h, was suppressed in smokers. These findings may explain the greater fatigue in smokers, which can increase risk for injury. p65 activity, suppressed at 48h in non-smokers, was unchanged in smokers, suggesting delayed pro-inflammatory resolution. Active and total ERK levels were suppressed, overall, in smokers. While there were no differences in NGF levels or colocalization with the TrkA receptor between smokers and non-smokers, smokers did express higher p75NTR receptor levels, which may activate NFκB and promote hyperalgesia. NGF/p75NTR co-localization at 48h post-ECC decreased in nonsmokers but increased in smokers. Higher DOMS, NGF, and NFκB signaling may indicate prolonged pro-inflammatory signaling, delayed resolution, and protracted healing in smokers. This dissertation provides insights into mechanisms that appear to place smokers at greater risk for musculoskeletal injury and impaired healing.