Connections between tau and nucleic acids have been largely underestimated until recently when several reports highlighted new key roles of tau in relation with DNA and RNA structure, metabolism and integrity, and their implications in the context of tauopathies. Here we focus on recent advances involving tau and nucleic acids in neuronal and non-neuronal cells. Implication of tau and tau pathology in mechanisms regulating genome integrity, chromatin organization and RNA metabolism, highlight the connections between tau and nucleic acid as major mechanisms in neuronal homeostasis and the etiopathology of tauopathies.