Metabolic diseases comprise a growing list of diseases like diabetes, cardiovascular disease and cancer. These diseases are referred to as complex diseases because they are strongly heritable, yet unlike simple monogenic diseases, they are due to multiple mutations affecting many genes in the genome. GWAS has been valuable in identifying candidate loci but so far in the case of diabetes these genetic risk factors account for 2-5% of the entire risk that is attributed to family history. Another factor in the emergence of these diseases is lifestyle particularly excess calories and insufficient exercise. During my lecture I will present information that there is no one single ideal lifestyle for humans due to genetic diversity. Hence, this represents what I believe to be one of the most challenging and intriguing problems in biology – dissecting the gene x environment interaction. A case will be made that this is a classic systems biology problem requiring a combination of both large scale and focused studies in model systems as well as in humans.