Chronic obstructive pulmonary disease (COPD) and other chronic diseases such as heart failure are accompanied by skeletal muscle alterations that further enhance morbidity and mortality in affected individuals. Several studies have highlighted important structural and biochemical modifications in limb and respiratory muscles in COPD. Reviewing the similarities and differences between the two most studied muscles in COPD, the quadriceps and the diaphragm, may be helpful in providing important clues about the mechanisms underlying muscle changes associated with this disease. Although oxidative stress is present in both muscles, other muscle alterations are clearly distinct between the quadriceps and the diaphragm. For example, the oxidative metabolism varies in opposite directions, the diaphragm exhibiting increased resistance to fatigue while the quadriceps in COPD is characterized by premature fatigability. Differences in muscle phenotypic expression between the diaphragm and the quadriceps indicate that, in addition to systemic factors, the local microenvironment must participate in the reorganization seen in these two skeletal muscles in COPD.