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Variability in the susceptibility to develop chronic obstructive pulmonary disease (COPD) is related to both genetic and environmental factors. COPD is likely a genetically complex disease, but severe alpha 1-antitrypsin (AAT) deficiency [e.g., protease inhibitor (PI) Z] remains the only proven genetic risk factor for COPD. Even among PI Z individuals, substantial variability in lung function is observed, suggesting that genetic modifiers may influence the expression of lung disease in severe AAT deficiency. The variable development of COPD in smokers without alpha 1-antitrypsin deficiency and the familial aggregation of lung function measurements also suggest the presence of genetic influences on lung function growth and decline leading to COPD. Many candidate gene loci have been investigated as potential COPD genetic determinants by case-control genetic association studies. However, inconsistent results of these association studies have been frequent. Genetic heterogeneity and population stratification are two potential reasons for the conflicting findings between association studies. Linkage analysis studies have recently been published that may identify regions of the genome that contain COPD susceptibility genes. Future investigations of genetic influences in COPD should consider the use of family-based designs for association studies and the study of positional candidate genes within regions of linkage.