The neuron-restrictive silencer factor (NRSF) a transcriptional regulator that function as a hub that coordinately regulates multiple aspects of neurogenesis, orchestrates neural differentiation, and preserves the unique neural phenotype. NRSF also acts as an oncogene in neural tumorigenesis, although its effect differs depending on the cell type and tissues. Intriguingly, far more than above functions, potential roles for NRSF and its target genes have also been implicated in the pathogenesis and therapeutic mechanism of neurodegenerative diseases. NRSF acts as a flexible and complicated regulator in nervous system, from transcriptional repressor to activator or modulator, and plays a part in neuronal survival or neuronal death. Here, we present the mechanisms proposed to account for the multiple roles of NRSF in neurogenesis and neurological diseases and discuss the therapeutic perspective of recent advances. The mechanisms underlying this duality of NRSF are helpful to understanding the physiological and pathological conditions of neurons and provide new therapeutic approaches to neurological disorders and diseases.