The LifeLines Cohort will investigate a representative sample of 165 000 participants from the three northern provinces of the Netherlands in a unique three-generation design. LifeLines is ‘hypothesis-driven’, i.e. all data collection and analyses are performed on the premise of specific research questions. Our central hypothesis is that the interaction between universal, generic risk factors and specific modifiers, e.g. Genetic, environmental and complex factors, accounts for the development of specific single disorders and for clustering of multiple disorders in individuals. Our explicit aim of investigating risk factors that apply across disorders constitutes a challenge to better understanding of the origins of health and disease over a lifetime. This change in paradigm may ultimately lead to better treatment of individual diseases and preventive strategies across diseases, as well as novel targets for intervention. The LifeLines Cohort aims at the following scientific breakthroughs: 1) Discover how social, biomedical, including genetic, and environmental factors are associated with long-term health and the development and progression of disease. 2) Assess why diseases cluster within individuals and families 3) Discover how genetic and environmental factors influence the development of disease during the course of life, i.e. discover dynamic risk profiles 4) Apply acquired insights to novel approaches aimed at ‘true’ primary prevention. 5) Identify effective interventions to reduce burden of disease and development of co-morbidities.