To develop an efficient therapy for chronic obstructive pulmonary disease (COPD), N-acetylcysteine (NAC) has been tested as a medication that can suppress various pathogenic processes in this disease. NAC is a thiol compound, which provides sulfhydryl groups. NAC can act as a precursor of reduced glutathione and as a direct reactive oxygen species scavenger, hence regulating the redox status in the cells. In this way NAC can interfere with several signaling pathways that play a role in regulating apoptosis, angiogenesis, cell growth and inflammatory response. Mucus hypersecretion has been reported in COPD and in other respiratory conditions. Two pathological processes have been described to play an important role in COPD, namely oxidative stress and inflammation. Both of these processes can induce mucin gene expression leading to mucin production. NAC, therefore, may influence mucin expression by acting on oxidative stress and inflammation, and play a role as a mucolytic agent. In this review we focus on the mucolysis of NAC in the management of COPD.