Adipose triglyceride lipase (ATGL) is required for efficient mobilization of fatty acids from cellular triglyceride stores. This central role in lipolysis marks ATGL as an interesting pharmacological target as deregulated fatty acid metabolism is closely linked to dyslipidemic and metabolic disorders. Based on preliminary structureactivity relationship (SAR) data we propose the design, synthesis, identification, and characterization of small-molecule inhibitors of human ATGL (hATGL). As no 3Dstructure is yet available for ATGL, we will pursue a classic medicinal chemistry approach in which compounds will be synthesized and tested to establish the SAR and optimize the properties of the inhibitor. The resulting molecular probe will be of tremendous value for studying the role of hATGL in lipid metabolism and metabolic disorders.