In this presentation I describe some of the approaches we are taking to identify the genetic architecture of common complex cancers with a particular focus on the etiology of lung cancer. Cancers results from joint effects of germline susceptibility along with common environmental exposures that propel risk for further stages of cancer development for some individuals. Genome-wide association studies have been highly effective in providing new insights into the etiology of these cancers. For lung cancer, genome-wide association analysis identified a key region of chromosome 15q that contains variants of nicotinic acetyl choline receptors that are expressed at low levels in most of the brain except a few selected areas, so these were not considered as primary candidates for smoking behavior nor for lung cancer risk. Further study of these loci shows they play a key role in lung cancer development as well as in tobacco use and smoking cessation. In particular, individuals with high risk variants have particular difficulty in tobacco cessation unless provided with pharmacological support. Other findings from genetic analysis of lung cancer have shown dramatic heterogeneity by histological subtype. A region on chromosome 5p21 harboring hTERT and CLPTM1L shows heterogeneity by histology, but animal models show that CLPTM1L plays a role in cancer progression. Finally, we discuss the role of sequencing for understanding the genetic architecture of cancers and how the limited resources available for genetic analysis might be applied for both sequencing and genome-wide assessment.