Chemoprevention of colorectal cancer has been the focus of intensive research for more than two decades. Epidemiological evidence has shown a small, but significant association between fruit and vegetable intake and a reduction in colorectal cancer risk. In vitro and animal data have also demonstrated that many dietary phytochemicals have potent chemopreventive activities. However, in humans, single-agent compounds have yielded conflicting results. A key concept is that dietary phytochemicals exert beneficial effects at low concentrations when working in synergy with each other. As the gut microflora evolved in an environment rich in dietary fiber and phytochemicals, the rapid shift towards a Western diet creates an environment in which the gut is more vulnerable to carcinogens, genetic alterations and inflammation. As enforcing dietary interventions on large populations is not realistic, we believe future chemopreventive work should focus on delivering phytochemical mixtures that target the multiple molecular events involved in colorectal carcinogenesis.