Endocrinology is an intrinsically integrative discipline, and is well suited to study in organisms in which genetic intervention is possible; indeed, such integrative physiology is actually a subset of functional genomics. Drosophila, with its powerful genetic technologies and accessible renal system, makes an ideal organism for studies both of fundamental and applied biology, as well as a model with predictive value for the vast Class of Insects. This review illustrates the application of molecular genetic and transgenic technologies available for work in Drosophila to the study of homeostasis by the renal (Malpighian) tubules. This has furthered our understanding of cell-specific signal transduction mechanisms and transport processes linked to epithelial renal function, which is under complex neuroendocrine control. The insights gained in Drosophila have proved applicable and relevant to other insects, and perhaps beyond.