Branching tubulogenesis of the ureteric bud, which gives rise to the urinary collecting system, is of considerable clinical interest because this process plays a major role in determining nephron number in the kidney. Data from in vitro model systems, including organ culture of the embryonic kidney and renal epithelial cells cultured in three-dimensional collagen matrices, indicate that growth factors, extracellular matrix composition, matrix-remodeling proteinases, and integrin expression are important factors in tubulogenesis and branching in the renal epithelium. One possibility is that gradients of soluble factors in the interstitial milieu of the embryonic kidney regulate the directionality of tubulogenesis and the degree of branching. Growth factors that enhance branching also appear to up-regulate matrix-remodeling extracellular proteinases. Redundancy in the ability of growth factors to induce tubulogenesis and branching may explain the apparent lack of a renal phenotype observed in targeted growth factor gene deletion experiments in mice. At the same time, differential effects in the efficiency of growth factors in inducing branching and/or changes in local matrix composition may be important in regulating the degree of arborization of the developing collecting system.