<p>The repressor element 1-silencing transcription factor (REST), or neuron-restrictive silencer factor (NRSF), is crucial for gene regulation since it binds to chromatin and recruits chromatin-modifying enzymes. Acting as a regulatory hub, REST orchestrates neurogenesis, neuronal differentiation, and the preservation of neuronal identity by regulating a broad network of target genes across stem cells, non-neuronal cells, and neurons. These targets influence critical processes such as axonal growth, vesicular transport, neurotransmitter release, and ion conductance. An important feature of normal aging in cortical and hippocampal neurons is REST induction, where it contributes to extended longevity by repressing genes linked to neuronal excitability and stress vulnerability. However, REST’s role in neurodegenerative diseases remains complex and context dependent. Variations in its expression and subcellular localization, including cytoplasmic translocation or loss, have been implicated in the pathology of disorders like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, schizophrenia, and epilepsy. Given its broad regulatory functions, REST has emerged as an attractive therapeutic target. Strategies such as microRNA modulation, small molecule inhibitors, and complex-disrupting compounds have been explored, each offering unique opportunities and challenges. Understanding REST’s molecular mechanisms and disease-specific functions is critical for identifying novel therapeutic interventions. This review provides a comprehensive analysis of REST’s role in aging and neurodegeneration, highlighting its regulatory networks, disease relevance, and recent therapeutic strategies targeting REST, with an emphasis on their potential for clinical translation.</p>