Studies of cell lines and some cultured neurons have demonstrated potential cross-talk between neurotrophins and their receptors; high concentrations of neurotrophins can exhibit either agonist or antagonistic actions on heterologous neurotrophin receptors. We have studied neurotrophin discrimination among the sensory neurons of the embryonic chicken trigeminal system. We show that nerve growth factor (NGF) at a concentration that is six orders of magnitude greater than that required to promote the survival of NGF-dependent dorsomedial trigeminal ganglion (DMTG) neurons has no effect on the survival of brain-derived neurotrophic factor (BDNF)-dependent trigeminal mesencephalic nucleus (TMN) neurons and does not affect the dose-response relationship of these neurons to BDNF. A similar high level of neurotrophin-3 neither promotes the survival of BDNF-dependent ventrolateral trigeminal ganglion neurons nor affects the dose response of these neurons to BDNF. High levels of BDNF have a negligible effect on the survival of mid-embryonic DMTG neurons. These results show that some neurons are able to discriminate completely between neurotrophins at very high concentrations, indicating that neurotrophin responses can be far more highly specific than previously appreciated.