Electronic cigarettes (e-cigarettes) have the potential to reduce the harm caused by smoking, but there is currently little information regarding their long-term safety. We propose a novel methodology to quantify aspects of the biological (specifically epigenetic) changes associated with e-cigarette use, and the extent to which these changes are associated with future disease risk. We will determine whether e-cigarette users (“vapers”) are more comparable to smokers of tobacco cigarettes or to never-smokers with respect to their epigenetic signature. We will then determine whether the epigenetic profile associated with e-cigarette use differentially predicts risk of disease, and whether these epigenetic changes are causally linked to disease, and as such may be targets for preventative interventions. This research will provide key scientific insights, as well as valuable information to both cigarette smokers and vapers regarding the relative safety of these products in relation to their biological impact and future disease risk.