COPD is a complex multisystem disease often accompanied by multiple co-morbidities that contribute to symptoms, exacerbations, hospital admissions and mortality. Individual comorbidities can be grouped into clusters of common human pathology: inflammation/immune response (e.g., ischemic heart disease, metabolic syndrome), thrombosis/hemorrhage (e.g., cerebrovascular diseases, pulmonary embolism), fibrosis/cell proliferation (e.g., lung cancer and other malignancies) and apoptosis/necrosis (e.g., osteoporosis, skeletal muscle dysfunction). While the prevalence of the co-morbidities has been described in a number of observational studies, there is considerable variability in results; moreover characterization of cluster of co-morbidities with the most clinical significance in terms of morbidity and mortality is still lacking. Pathological mechanisms underlying some of the identified clusters are well known; others need further clarification to identify possible preventative strategies. Treatment of COPD must include management of the underlying co-morbidities for best outcomes.