Abstract Neurodegeneration is one of the greatest public health challenges for the 21st century. Among neurodegenerative diseases, Alzheimer’s disease (AD) is the most prevalent and best characterized. Nevertheless, despite the large investment in AD research, currently there is no effective therapeutic option. In the present review, we highlight a novel alternative, which takes advantage of the biotechnological outbreak deployed by the discovery of the RNA interference-based gene silencing mechanism, and its application as a tool for neurodegeneration treatment. Here, we highlight cyclin-dependent kinase 5 (CDK5) as a key candidate target for therapeutic gene silencing. Unlike other members of the cyclin-dependent kinase family, CDK5 does not seem to play a crucial role in cell cycle regulation. By contrast, CDK5 participates in multiple functions during nervous system development and has been established as a key mediator of Tau hyperphosphorylation and neurofibrillary pathology, thus serving as an optimal candidate for targeted therapy in the adult nervous system. We propose that the use of RNA interference for CDK5 silencing presents an attractive and specific therapeutic alternative for AD and perhaps against other tauopathies.