Cigarette smoking and poor air quality are the greatest risk factors for developing chronic obstructive pulmonary disease (COPD), but growing evidence indicates that genetic factors also affect predisposition to and clinical expression of disease. With the exception of α1-antitrypsin deficiency (AATD), a rare autosomal recessive disorder that is present in 1–3% of individuals with COPD, no single gene is associated with the development of obstructive lung disease. Instead, a complex interplay of genetic, epigenetic, and environmental factors is the basis for persistent inflammatory responses, accelerated cell aging, cell death, and fibrosis, leading to the clinical symptoms of COPD and different phenotypic presentations. In this brief review, we discuss current understanding of the genetics of COPD, pathogenetics of AATD, epigenetic influences on the development of obstructive lung disease, and how classifying COPD by phenotype can influence clinical treatment and patient outcomes