Enzymes which interact with lipids (such as lipases, phospholipases, lipid kinases, etc.) are of interest as drug targets as they typically play important roles in metabolic and cardiovascular function. A unique feature of these enzymes is that they perform their chemistries in the context of an interface; this results in distinct kinetics from soluble enzymes, and presents a challenge in understanding the mechanism of action for drug candidates. We describe the development and applications of methodologies designed to address the mode of action of inhibitors of endothelial lipase, an interfacial enzyme mainly responsible for the catabolism of HDL (the �good� cholesterol). Active site protection experiments wtih an irreversible inactivator are presented.