Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive obstruction of airflow affecting peripheral airways. The proteomic analysis highlights ways to identify novel biomarkers for diagnosis, therapy, and prognosis in COPD. Human samples, for example, lung tissue, bronchoalveolar lavage, sputum, and serum, have been used for COPD proteomic research, each with its own merits and demerits. In the present review, we aimed at discussing the feasibility of clinical studies on COPD proteomics and the potential candidates for COPD biomarkers detected in human samples that are sensitive to the progress of COPD, disease-specific to COPD, and associated with the status of the patients. There is an increasing need to be able to perform proteomic studies on patients with COPD that describe the association with disease specificity, severity, progress, and prognosis as well as monitor the efficacy of therapies. There is an urgent need to establish and clarify the criteria for subjects including controls and data analysis and standardize the study design, methodology, and process as this is vital when designing prospective clinical studies on COPD. It is important to clarify the source of the samples, the efficiency, and quality when dealing with large amount of candidates and the specificity of biomarkers according to the severity, therapeutic effects, progress, and prognosis of the disease.