Two recent studies identified TM6SF2 as a regulator of liver triglyceride content (Nat. Genet. 46, 352–356, 2014) and plasma total cholesterol levels (Nat. Genet. 46, 345–351, 2014) through exome-based association analyses and functional experiments in mice. In independent work, Ferdinand van't Hooft and colleagues (Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.1323785111, 4 June 2014) performed a series of subcellular localization, knockdown and overexpression studies in cultured cells to gain further insights into TM6SF2 function. Using confocal microscopy, they observed localization of GFP-tagged TM6SF2 to the endoplasmic reticulum in two human hepatoma cell lines. They further showed that knockdown of TM6SF2 in both cell lines resulted in reduced secretion of triglyceride-rich lipoproteins and increased cellular triglyceride levels. At the subcellular level, they observed a marked increase in lipid droplet area, which could be attributed to increases in both the number and average size of lipid droplets. Conversely, they found that overexpression of TM6SF2 caused a decrease in the number and average size of lipid droplets. These results suggest a role for TM6SF2 in regulating the supply of lipids for the synthesis of triglyceride-rich lipoproteins.