Mammalian kidney development requires the formation of a patterned, branched network of collecting ducts, a process termed renal branching morphogenesis. Disruption of renal branching morphogenesis during human kidney development results in renal dysplasia, the major cause of renal failure in young children. Genetic evidence, combined with in vitro data, have implicated transcription factors, secreted growth factors, and cell surface signaling peptides as critical regulators of renal branching morphogenesis. This review discusses the current knowledge regarding the regulation of renal branching morphogenesis in vivo provided by the analysis of genetic mutations in mice and humans which disrupt collecting duct system development. In addition, in vivo and in vitro evidence regarding the functions of several other gene families are considered, rendering new insight into emerging regulatory roles for these molecules in renal branching morphogenesis.