The mammalian kidney forms from several populations of progenitors that only persist during embryogenesis. The epithelial nephron progenitors reside in the cap mesenchyme (CM), whereas mesangial and endothelial cell progenitors reside in the neighboring stromal mesenchyme (SM). After a ureteric bud (UB) signal induces mesenchymal to epithelial transition of some CM cells, they form a nascent epithelial ball (a renal vesicle, or RV) that requires signals mediated by Notch receptors to separate proximal from distal fates. Two Notch receptors (Notch1 and Notch2) and two ligands (Jagged1 and Delta1) are expressed in the RV. Notably, instead of providing sufficient redundancy to ensure that losing any one allele will be inconsequential to human health, a reduction in the dose of one ligand (Jagged1) or one receptor (Notch2) is causally associated with a rare developmental syndrome (Alagille syndrome, or ALGS) affecting eye, kidney, liver, and craniofacial development. Here we discuss our current understanding of the molecular basis for the nonredundant role of Notch2 in this process, and the avenue for new therapeutic strategies that these insights provide.