COPD is a highly prevalent disorder that results from the interplay of genetic susceptibility and environmental exposures. Over the past 2 decades, significant technological advances have been made in genetic investigations of complex diseases, yet limited progress has been made in the identification of additional COPD susceptibility genes. Genetic and phenotypic heterogeneity, limited power due to modest study population sizes, and significant modification of genetic effects by environmental factors pose significant challenges in COPD and emphysema genetic studies. More refined characterization of the emphysema and airway components of COPD can now be obtained through the systematic use of CT scans. These improved phenotypes can be applied in genome-wide association studies and will likely lead to the discovery of additional susceptibility loci and therapeutic targets.