Because of the limited therapeutic applications of nerve growth factor (NGF), there has been increasing focus on the development of pharmacological tools to bypass the requirement of NGF for the activation of the TrkA tyrosine kinase receptor neuronal survival pathway. In this issue of Molecular Pharmacology, the work by Culmsee et al. (p. 1006) shows that NGF-independent activation of TrkA by protein tyrosine phosphatase (PTP) inhibitors is only achieved when accompanied by release of nitric oxide (NO). This work identifies the integration of the NO/cGMP/protein kinase G (PKG) and NGF/TrkA pathways to induce activation of Akt and ERK1/2 and mediate neuronal survival in the absence of NGF. In addition, it underscores the potential therapeutic effects of ethyl-3,4-dephostatin (DPN), a stable analog of the naturally occurring PTP inhibitor dephostatin, which serves as a NO donor and protects neurons from apoptosis. This Perspective comparatively reviews two major signal transduction pathways that mediate NGF-independent neuronal survival by activating the TrkA pathway: the NO/cGMP/PKG and adenosine/G-protein-coupled receptor (GPCR) pathways.