The Environment And Genetics in Lung cancer Etiology (EAGLE) study is a large population-based case-control study that includes behavior, treatment and survival information in addition to the traditional epidemiological and biomarker data to elucidate exposure, gene, and disease links. EAGLE consists of 2100 incident, primary lung cancer cases, and 2120 population-based controls enrolled in Italy. Epidemiological analyses showed etiologic differences by histology for smoking, occupation, nonmalignant lung diseases and meat intake. Family history of lung cancer, family history of smoking, and SNPs in metabolic genes also showed different risks by histology. A genome-wide association study (GWAS), including EAGLE and ~1700 subjects from the PLCO cohort and other studies identified a locus on chromosome 5p15.33 (in the TERT region) associated with adenocarcinoma risk. In a pathway analysis we also identified a new locus on chrom 12p (in the RAD52 region) associated with squamous cell carcinoma risk. Imputation based on the recent 1000 Genome projects revealed three new loci, around the BRCA2, CHECK2 and TP63 genes. Fine mapping of the main susceptibility loci, including also the HLA region, is ongoing. Analyses of smoking phenotypes identified the time to first cigarette (TTFC) as a very important variable for lung cancer risk, independent from other tobacco smoking measures. We found a strong gene expression smoking signature in adenocarcinoma and noninvolved lung tissue that was associated with lung cancer risk and survival. Genome-wide methylation analyses identified an unprecedented genetic control of the human methylome. microRNA analyses in blood and tissue from the same subjects are ongoing. We are currently conducting analyses of tumor genetic alterations and integrate results with GWAS and clinical data.