Systems genetics is a novel approach for identifying the complex genetic architecture of quantitative traits and gene-environment interactions via detection of connections from genetic variation through intermediate phenotypes to overlying systems level phenotypes. This symposium, conducted at the Experimental Biology 2010 conference, aimed at educating nutrition researchers about the use of systems genetics as a tool for linking genetic variation to nutrient metabolism and energy balance and their overlying effects on health and disease. Basic concepts of systems genetics and the analytical framework used in these studies were presented. Further, the utility of genetic reference populations for gene-environment interaction studies along with specific studies addressing genetic variation in responsiveness to nutrients were discussed.