Zinc release is a primary mediator of neuronal death. Here we show that zinc-mediated death of neurons in vitro is dependent on nerve growth factor (NGF) stimulation and does not occur in response to exposure to leukemia inhibitory factor. NGF priming is regulated, not by the traditional neurotrophin death receptor, p75NTR, but by TrkA, in a protein- and mRNA synthesis-dependent manner. Furthermore, Trk signaling promotes raised free intracellular zinc, mediating neuronal death after extracellular application of zinc. Thus, regulators of Trk signaling provide attractive targets for future treatment of zinc-associated neurological diseases, including stroke, epilepsy and brain trauma.