ABSTRACT The Clinical and Biomarkers Core is critical for the studies in this program project renewal proposal. The Core will run clinical trials to collect biological samples and will carry out analyses of tobacco constituent biomarkers. The Clinical Trial component of this Core includes trained personnel with clinical research and implementation expertise that will be applied to conduct the clinical trials proposed in Projects 2 and 4. Both trials include the use of stable isotope-labeled constituents. Project 2 will use oral administration of [pyridyl-D4]-nicotine to develop a CYP2A6 genetic score that will allow to predict nicotine metabolism in smokers. This study will recruit 400 smokers (Native Hawaiians, Japanese Americans, Whites, and African Americans) in Hawaii and Minnesota. Project 4 will administer [D10]phenanthrene and [13C18]linoleic acid to 50 never smokers and 50 formers smokers, to investigate the potential contribution of metabolic and inflammatory pathways to the elevated risk for lung cancer in former smokers. The Biomarkers component of the Core will analyze a panel of biomarkers of exposure and effect. These will include total nicotine equivalents, cotinine, total 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol, phenanthrene tetraol, and mercapturic acids of acrolein, crotonaldehyde, and propylene oxide, and urinary cadmium (Cd) in urine samples collected in clinical trials. Plasma nicotine metabolite ratio will be also measured. Results of these analyses will be used by Projects 2, 3, and 4. In addition, biomarkers of potential harm (urinary and blood-based biomarkers relevant to oxidative stress and inflammation) will be measured for Projects 3 and 4. The Core will also assess urinary Cd in 1000 samples from Project 1. The biological samples and biomarker results generated by this Core will be used by all projects.