Diet-health relationships are difficult to substantiate, mostly because effects of dietary changes are relatively subtle and may become apparent only at the long term. Human clinical trials to support health benefits of food supplements in the healthy population are generally large-sized studies, requiring substantial investments. There is a large gap between preclinical work, and the generation of evidence in humans. The concept of flexibility in the response to stress is used in so-called challenge tests that have been introduced in nutrition and health research to evaluate the impact of dietary interventions. Human challenge models can be used to reduce the risk of failure in field trials. In these smaller-sized trials, a controlled challenge is provided to healthy subjects, to measure the effect of food ingredients on resilience to the stressor. Metabolism may for instance be challenged by the acute intake of a high amount of fat or glucose, or by strenuous exercise. For infection resistance, we apply an E. coli challenge model (gut infection), a rhinovirus challenge model (upper respiratory tract infection), and a vaccination model (immune function related to infection resistance). The challenge concept will be illustrated with examples of published intervention studies.