Chronic obstructive pulmonary disease (COPD) is a clinically heterogeneous syndrome characterized by injury to airways, airspaces and lung vasculature and usually caused by tobacco smoke and/or air pollution exposure. COPD is also independently associated with non-pulmonary comorbidities (e.g. cardiovascular disease) and malignancies (e.g. gastrointestinal and bladder), suggesting a role for systemic injury. Since not all those with exposure develop COPD, there has been a search for plasma and lung biomarkers that confer increased cross-sectional and longitudinal risk. This search typically focuses on clinically-relevant COPD outcomes such as forced expiratory volume at 1 second (FEV1), FEV1 decline, computer tomography (CT) measurements of emphysema, or exacerbation frequency. The rapid advances in omics technology and the molecular phenotyping of COPD cohorts now permit large-scale evaluation of genetic, transcriptomic, proteomic, and metabolic biomarkers. This review focuses on protein biomarkers associated with clinically-relevant COPD outcomes. The prototypic COPD protein biomarker is alpha-1 antitrypsin; however, this biomarker only accounts for 1-5% of COPD. This manuscript reviews and summarizes the evidence for other validated biomarkers for each COPD outcome, and discusses their advantages, weaknesses, and required regulatory steps to move the biomarker from the bench into clinic. While we highlight the emergence of many novel biomarkers [e.g. fibrinogen, soluble Receptor for Advanced Glycation (sRAGE), Surfactant Protein D (SP-D), Club Cell Secretory Protein (CC16)], there is increasing evidence that individual biomarkers only explain a fraction of the increased COPD risk and that multiple biomarker panels are needed to completely explain clinical variation and risk in individuals and populations.