Neurotrophic factors control the survival, differentiation and maintenance of neurons in the peripheral and central nervous systems. Their discovery and characterization have been instrumental to our understanding of a wide range of phenomena in the development, plasticity and repair of the nervous system. Their potential importance in the development of therapeutic agents against neurodegenerative disorders and nerve injury has led to a flurry of activity towards understanding their structure, function and signaling mechanisms. This knowledge has increased dramatically in recent years, in particular due to the elucidation of three-dimensional structures, the discovery of families of structurally related neurotrophic factors and the characterization of receptors and downstream signaling components. Common themes are emerging from these recent studies that allow us to make new insights and predictions as to the function and possible clinical utility of these molecules.