Epidemiological studies have consistently shown that regular consumption of whole grain barley reduces the risk of developing chronic diseases. The presence of barley fiber, especially β-glucan in whole grain barley, has been largely credited for these health benefits. However, it is now widely believed that the actions of the fiber component alone do not explain the observed health benefits associated with the consumption of whole grain barley. Whole grain barley also contains phytochemicals including phenolic acids, flavonoids, lignans, tocols, phytosterols, and folate. These phytochemicals exhibit strong antioxidant, antiproliferative, and cholesterol lowering abilities, which are potentially useful in lowering the risk of certain diseases. Therefore, the high concentration of phytochemicals in barley may be largely responsible for its health benefits. This paper reviews available information regarding barley phytochemicals and their potential to combat common nutrition-related diseases including cancer, cardiovascular disease, diabetes, and obesity.