Over the last decades the burden of disease in Western countries has shifted from comparably easily treated infectious diseases to more complex diseases, such as the metabolic syndrome, cardiovascular disease, and psychiatric disorders. A common characteristic of these illnesses is the interplay of multiple genetic and nongenetic factors, which eventually results in the manifestation of disease symptoms. Large-scale epidemiological studies in humans have resulted in the identification of various environmental and genetic risk factors, which contribute to the onset, duration, and severity of disease. While tremendous progress has been made, it is still impossible to predict which combination of risk factors will result in the manifestation of a specific illness. This lack of knowledge is also frequently reflected in inadequate treatment strategies, which mainly focus on symptom reversal rather than targeting the cause of the diseases. One of the most prominent environmental risk factors described for numerous diseases is chronic exposure to stressful situations. In this paper we address clinical and preclinical evidence of chronic stress as a risk factor for disease and introduce a novel, high-throughput mouse model for chronic social stress. We can show that this model has a high degree of construct, face, and predictive validity in terms of physiological, behavioral, and gene expression changes. We further illustrate how novel animal models of chronic social stress can help to unravel the complex interaction of individual genetic vulnerability and environmental risk factors.