In most countries, non-communicable diseases have taken over infectious diseases as the most important causes of death. Many non-communicable diseases that were previously lethal diseases have become chronic, and this has changed the healthcare landscape in terms of treatment and prevention options. Currently, a large part of healthcare spending is targeted at curing and caring for the elderly, who have multiple chronic diseases. In this context prevention plays an important role, as there are many risk factors amenable to prevention policies that are related to multiple chronic diseases. This article discusses the use of simulation modeling to better understand the relations between chronic diseases and their risk factors with the aim to inform health policy. Simulation modeling sheds light on important policy questions related to population aging and priority setting. The focus is on the modeling of multiple chronic diseases in the general population and how to consistently model the relations between chronic diseases and their risk factors by combining various data sources. Methodological issues in chronic disease modeling and how these relate to the availability of data are discussed. Here, a distinction is made between (a) issues related to the construction of the epidemiological simulation model and (b) issues related to linking outcomes of the epidemiological simulation model to economic relevant outcomes such as quality of life, healthcare spending and labor market participation. Based on this distinction, several simulation models are discussed that link risk factors to multiple chronic diseases in order to explore how these issues are handled in practice. Recommendations for future research are provided.