During development, each tissue receives and maintains a number of specific neuronal projections that are adequate to sustain its function. The mechanism by which this intricate process occurs is not well understood, but it has been proposed that diffusible neurotrophic factors derived from the target tissue may be involved. Here we describe the identification of a novel human protein that is important for the growth, differentiation, and survival of primary sympathetic and placode-derived sensory neurons. This polypeptide, designated neuronotrophin-3, has a broad tissue distribution and is structurally related to both nerve growth factor and brain-derived neurotrophic factor. Its unique range of trophic and differentiation-inducing activities suggests that it is likely to play a wide role in defining the fate and function of nerve cells during development.