The German National Cohort (GNC) is a joint interdisciplinary endeavour of scientists from the Helmholtz and the Leibniz Association, universities, and other research institutes. Its aim is to investigate the causes for the development of major chronic diseases, i.e. cardiovascular diseases, cancer, diabetes, neurodegenerative/-psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases, and their pre-clinical stages or functional health impairments. Across Germany, a random sample of the general population will be drawn by 18 regional study centres, including a total of 100,000 women and 100,000 men aged 20-69 years. The baseline assessments include an extensive interview and self-completion questionnaires, a wide range of medical examinations and the collection of various biomaterials. In a random subgroup of 20 % of the participants (n = 40,000) an intensified examination ("Level 2") programme will be performed. In addition, in five of the 18 study centres a total of 30,000 study participants will take part in a magnetic resonance imaging examination programme, and all of these participants will also be offered the intensified Level 2 examinations. After 4-5 years, all participants will be invited for a re-assessment. Information about chronic disease endpoints will be collected through a combination of active follow-up (including questionnaires every 2-3 years) and record linkages. The GNC is planned for an overall duration of 25-30 years. It will provide a major, central resource for population-based epidemiology in Germany, and will help to identify new and tailored strategies for early detection, prediction, and primary prevention of major diseases.