The lipid droplet (LD) is a unique cellular organelle containing a neutral-lipid core enclosed by a phospholipid monolayer and associated proteins. Despite the important function of LDs at the hub of cellular energy homeostasis regulation, major questions in the field of LD biology are still unanswered. Drosophila melanogaster has been used as a model organism to make fundamental discoveries in biology for over a century. In recent years, genome-wide unbiased reverse genetic screens using Drosophila cells or transgenic lines have been proven to provide valuable knowledge to the field of LD biology. Here we summarize the methods we use for functional genomic screens in Drosophila S2 cells to identify genes involved in LD biology, and the methods used for studying LD function in vivo using Drosophila as a model to combat metabolic diseases.