The repressor element 1 (RE-1)-silencing transcription factor (REST), also known as the neuron-restrictive silencer factor (NRSF), was originally discovered as a transcriptional repressor of a large number of primarily terminal neuronal differentiation genes in nonneuronal cells and neural stem cells (NSCs). Although REST is expressed in NSCs, its transcription is generally blocked as NSCs undergo differentiation, and it is rarely expressed in terminally differentiated neurons. In support of its function as a transcriptional repressor, REST was found to contain a DNA-binding domain and two repressor domains. The repressor domains were found to associate, directly or indirectly, with a large number of cellular repressor complexes. Thus, REST was considered a major epigenetic regulator controlling chromatin modification. However, REST is expressed in some differentiated neurons, and when bound to a double-stranded small RNA, REST was later found to also function as an activator of its same target neuronal differentiation genes in NSCs. In addition, REST has been found to regulate an evolving array of genes and cellular functions, making it a biological enigma. For example, REST was recently found to have a seemingly paradoxical role in both tumor suppressor activity and oncogenic activity. Current evidence suggests that the diverse cellular context generated by intrinsic factors in the cell, the amount of REST protein present in the cell, the affinity of the REST protein for its specific target gene, and the cellular niche dictate such behavior.