Epidemiologic data support the association between high intake of vegetables and fruits and low risk of chronic disease. There are several biologically plausible reasons why consumption of vegetables and fruit might slow or prevent the onset of chronic diseases. Vegetables and fruit are rich sources of a variety of nutrients, including vitamins, trace minerals, and dietary fiber, and many other classes of biologically active compounds. These phytochemicals can have complementary and overlapping mechanisms of action, including modulation of detoxification enzymes, stimulation of the immune system, reduction of platelet aggregation, modulation of cholesterol synthesis and hormone metabolism, reduction of blood pressure, and antioxidant, antibacterial, and antiviral effects. Although these effects have been examined primarily in animal and cell-culture models, experimental dietary studies in humans have also shown the capacity of vegetables and fruit and their constituents to modulate some of these potential disease-preventive mechanisms. The human studies have relied on intermediate endpoints related to disease risk. Design methodologies used include multiple-arm trials, randomized crossover studies, and more compromised designs such as nonrandomized crossovers and pre- and posttreatment analyses. Length of treatment ranged from a single dose to years depending on the mechanism of interest. Stringency of dietary control varied from addition of supplements to a habitual diet to provision of all food for the duration of a treatment. Rigorously conducted experimental dietary studies in humans are an important link between population- and laboratory-based research.