Chronic obstructive pulmonary disease (COPD) is still a leading cause of morbidity and mortality worldwide, with a huge socioeconomic impact. New strategies for the management of COPD are required, not only for identifying the origin of the exacerbation episodes, but also to assess an individual risk for each patient. A promising approach is to measure systemic biomarkers and correlate their levels with exacerbation characteristics and clinical prognosis of the disease. Several biomarkers have clearly correlated with the aetiology of lower respiratory tract infections and the response to antibiotic treatment, indicating a potential utility in COPD exacerbation. Nevertheless, the results available at the moment, together with the absence of a gold standard for identifying the aetiological origin of an exacerbation, impedes establishing the real utility of these biomarkers for this concrete task. Regarding the clinical evolution and prognosis, several clinical characteristics have been correlated to biomarker levels. The potential influence of many factors (severity of the disease, presence of comorbidities and treatment) leads to the conclusion that, in the future, the best option would be to monitor levels individually, rather than establishing cut-off points for the general COPD population.