The neurotrophins neurotrophin-3 (NT-3), brain-derived growth factor (BDNF) and nerve growth factor (NGF) bind to the p75 receptor, but each neurotrophin also binds a more selective Trk receptor (e.g. TrkA-NGF and TrkC-NT-3). The biochemical signals following engagement of either Trk or p75 with ligands are well understood, but long-term biological outcomes (trophic, proapoptotic or differentiative) remain unclear because they are cell/tissue specific. For example, Trk receptors are usually trophic but when overexpressed they can be proapoptotic in neuroblastomas and medulloblastomas. We hypothesized that coexpression of Trk and p75 receptors may lead to cross-regulation of signals and different biological outcomes; and used receptor-selective ligands to study cross-regulation by these receptors. We show that in the absence of Trk activation, expression of TrkC is permissive of p75 trophic and differentiation signals induced by p75 ligands, whereas expression of TrkA abolishes trophic and differentiation signals induced by p75 ligands. In contrast, in the presence of Trk activation, p75 ligands can regulate TrkA-mediated survival and TrkC-mediated differentiation. Therefore, a complex homeostasis of p75-selective and Trk-selective signals may determine the fate of cells expressing both receptors.