Hyperlipidemia is an important risk factor for cardiovascular disease globally, but there is still much mystery surrounding the topic of lipid regulation. Many studies have attempted to assess the underlying genetic basis of low-density lipoprotein (LDL) metabolism. Recently, multiple genome-wide association studies identified genes that strongly associate with plasma lipid concentration and cardiovascular disease. Compelling evidence linking the SORT1 gene to both LDL cholesterol (LDL-C) levels and the risk of coronary artery disease emerged from the data, prompting the search for the molecules and mechanisms responsible for this association. Three recent studies explored this relation through sortilin, the gene product of SORT1, and an intracellular trafficking molecule. Careful, hypothesis-driven experimental designs elucidated the potential mechanisms of sortilin's role in LDL-C metabolism. However, each study's conclusions differed in the details of SORT1's association to LDL-C and the subcellular mechanisms at work. Nevertheless, these 3 studies demonstrate how a complex disease such as hyperlipidemia can be evaluated from the scope of the genome down through the level of cellular regulation. Their findings serve as a platform for further study of LDL-C metabolism and hyperlipidemia while also providing lessons on how to better study other complex diseases.