Since chronic obstructive pulmonary disease (COPD) has a progressive and major impact on health management, many aspects of this disorder, including development of effective and reliable biomarkers to monitor disease progression, are under intensive investigation. A huge amount of data, accumulated over the years, have provided solid evidence that two pyridinium-ring-containing amino acid isoforms, desmosine and isodesmosine (usually referred to as desmosines), unique to mature elastin in humans, are representative of the elastin breakdown occurring in chronic destructive disorders, such as COPD. This paper is aimed at providing a critical review of the methodological steps that have marked the progress in the detection of desmosines in biological fluids in health and disease, as well as the progress in the authors knowledge of desmosines’ role in the pathophysiology of COPD. The authors have tried to emphasize that the suitability of desmosine as a biomarker for COPD increased over the years, as the techniques developed for its detection became progressively more sophisticated and precise. The authors conclude that desmosines, although not yet definitely proven, have nevertheless all the requisites to become a critical COPD biomarker.