The epidemic of non-alcoholic fatty liver disease (NAFLD) in the United States is staggering, and there is an enormous void in our understanding of the clinical epidemiology other than the common themes of obesity and insulin resistance. There is also a public health need to better define effective treatments of NAFLD, including dietary interventions and appropriate nutritional supplements. There is, however, a wealth of basic science that helps to set the stage for defining the mechanisms leading to liver pathology. In this article we will attempt to put these concepts in perspective to highlight the need for future research including the use of medicinal food.