The neurotrophins are a family of trophic factors that have been shown to have neuroprotective effects after traumatic lesions of the nervous system and in animal models of neurodegenerative diseases. They mediate a broad spectrum of biological actions by interacting with tyrosine kinase receptors (Trk). While studies have demonstrated that neurotrophin administration may have beneficial effects, there were difficulties in delivering therapeutic quantities of these factors to spinal motor neurons. We now describe a strategy for applying transactivation of Trk receptors using small molecules, such as adenosine, which can penetrate the blood brain barrier and rescue motor neurons from cell death. Transactivation opens up the possibility of stimulating Trk receptors only in populations of neurons that co-express both Trk and adenosine receptors. We propose in this review to exploit transactivation to improve the survival of motor neurons in a transgenic mouse model of ALS and for other neurodegenerative diseases, such as Alzheimer's and Huntington's disease.