Branching morphogenesis, defined as growth and branching of epithelial tubules during embryogenesis, is a fundamental feature of renal, lung, mammary gland, submandibular gland, and pancreatic morphogenesis in mammals. Disruption of branching morphogenesis has been demonstrated to result in maldevelopment of some of these organs. Genetic studies performed in affected humans and mutant mice have implicated transcription factors, secreted growth factors, and cell surface signaling molecules as critical regulators of branching morphogenesis. These factors function within networks that appear to exert tight control over the number and location of branches. This review summarizes current knowledge regarding the molecular control of branching morphogenesis in vivo with particular emphasis on the genetic contribution to perturbed branching morphogenesis in mice and humans.