The risk for multifactorial diseases is determined by risk factors that frequently apply across disorders (universal risk factors). To investigate unresolved issues on etiology of and individual’s susceptibility to multifactorial diseases, research focus should shift from single determinant-outcome relations to effect modification of universal risk factors. We present a model to investigate universal risk factors of multifactorial diseases, based on a single risk factor, a single outcome measure, and several effect modifiers. Outcome measures can be disease overriding, such as clustering of disease, frailty and quality of life. “Life course epidemiology” can be considered as a specific application of the proposed model, since risk factors and effect modifiers of multifactorial diseases typically have a chronic aspect. Risk factors are categorized into genetic, environmental, or complex factors, the latter resulting from interactions between (multiple) genetic and environmental factors (an example of a complex factor is overweight). The proposed research model of multifactorial diseases assumes that determinant-outcome relations differ between individuals because of modifiers, which can be divided into three categories. First, risk-factor modifiers that determine the effect of the determinant (such as factors that modify gene-expression in case of a genetic determinant). Second, outcome modifiers that determine the expression of the studied outcome (such as medication use). Third, generic modifiers that determine the susceptibility for multifactorial diseases (such as age). A study to assess disease risk during life requires phenotype and outcome measurements in multiple generations with a long-term follow up. Multiple generations will also enable to separate genetic and environmental factors. Traditionally, representative individuals (probands) and their first-degree relatives have been included in this type of research. We put forward that a three-generation design is the optimal approach to investigate multifactorial diseases. This design has statistical advantages (precision, multiple-informants, separation of non-genetic and genetic familial transmission, direct haplotype assessment, quantify genetic effects), enables unique possibilities to study social characteristics (socioeconomic mobility, partner preferences, between-generation similarities), and offers practical benefits (efficiency, lower non-response). LifeLines is a study based on these concepts. It will be carried out in a representative sample of 165,000 participants from the northern provinces of the Netherlands. LifeLines will contribute to the understanding of how universal risk factors are modified to influence the individual susceptibility to multifactorial diseases, not only at one stage of life but cumulatively over time: the lifeline.