The kidney is the body’s filter, responsible for the removal of metabolic waste and the excretion or reabsorption of electrolytes to control blood composition and pH balance. The functional unit of this filter is the nephron, whose segmented architecture has been largely conserved in form and function throughout eukaryotic evolution. Not surprisingly, the core developmental pathways that regulate the formation of the nephron have also been conserved. In particular, the Notch signaling pathway functions in both primitive and advanced nephrons to pattern domains required for the kidney’s diverse functions. In this chapter, we will discuss the role that Notch plays in directing cell fate decisions during embryonic development of the pronephros and metanephros. We will go on to discuss the later role of Notch signaling as a cyst‑suppressor and the consequences of aberrant or absent Notch activity in disease and cancer. The work discussed here highlights the fundamental importance of Notch during development and homeostasis of the kidney and underlies the need for mechanistic understanding of its role towards the treatment of human disease.