There is ample scientific evidence suggesting that the health benefits of eating the right amounts of a variety of vegetables and fruit are the consequence of the combined action of different phytochemicals. The present review provides an update of the scientific literature on additive and synergistic effects of mixtures of phytochemicals. Most research has been carried out in in vitro systems in which synergistic or additive effects have been established on the level of cell proliferation, apoptosis, antioxidant capacity, and tumor incidence, accompanied by changes in gene and protein expression in relevant pathways underlying molecular mechanisms of disease prevention. The number of human dietary intervention studies investigating complex mixtures of phytochemicals is relatively small, but showing promising results. These studies have demonstrated that combining transcriptomic data with phenotypic markers provide insight into the relevant cellular processes which contribute to the antioxidant response of complex mixtures of phytochemicals. Future studies should be designed as short-term studies testing different combinations of vegetables and fruit, in which markers for disease outcome as well as molecular ('omics)-markers and genetic variability between subjects are included. This will create new opportunities for food innovation and the development of more personalized strategies for prevention of chronic diseases.