Peripheral muscle dysfunction associated with chronic diseases is undeniably a growing problem as one of its main causes, chronic obstructive pulmonary disease (COPD), progresses. Among others, muscle atrophy is one component building the concept of muscle dysfunction. Muscle atrophy has a significant impact on patient clinical status, independent of the impairment in lung function. A lot of effort has been devoted lately to increasing our understanding of the relationship between COPD and the initiation and the development of muscle atrophy. A growing body of evidence is showing that the ubiquitin-proteasome system, an ATP-dependent proteolytic pathway, is playing a crucial role in the cascade leading to degradation of contractile proteins, thus promoting the development of muscle atrophy. Interestingly, this system is also involved in essential cellular processes such as response to hypoxemia and muscle tissue regeneration. In this review, existing evidence linking the activity of the ubiquitin-proteasome system and the cellular events taking place in respiratory and peripheral muscles of patients with COPD are reported. Based on this information, the reader should be able to understand the essential role of this pathway in the context of muscle homeostasis and to picture the coming research in this area.