This essay discusses strategies for understanding the origins and outcomes of complex chronic inflammatory diseases using genetic and environmental determinants as tools for new definitions of disease subsets. Rheumatoid arthritis has been chosen as the prototype to illustrate these general concepts. Through recent data on two different disease subsets, it has been possible to devise a new molecular model for disease development by incorporating multiple genes and environmental agents which generate immune reactions that may eventually cause disease. These kinds of studies, aiming to integrate genetic epidemiology and molecular immunology, require close proximity between institutions for molecular medicine, clinical departments able to provide follow-up, careful surveillance of large patient groups and collaboration with experts in epidemiology and biostatistics.