In this commentary, we discuss evidence suggesting that cytoplasmic free calcium concentration determines neurotrophic factor dependence. Developing sympathetic and neural crest-derived sensory neurons require nerve growth factor (NGF) for survival both in vivo and in vitro. Chronic depolarization of these cells in culture causes a modest sustained elevation of cytoplasmic calcium concentration and promotes their survival in the absence of NGF. The amount of calcium increase caused by depolarization is closely correlated with the ability of the cells to survive in NGF-free medium. At an optimal calcium concentration, that we refer to as a "set point," survival is equivalent to that of cells grown in the presence of NGF.