Since its original discovery as a negative regulator of neuronal differentiation, the repressor element (RE)-1 silencing transcription factor (REST), also known as the neuron-restrictive silencer factor, has been implicated in novel processes such as maintenance of embryonic stem cell pluripotency and self-renewal and regulation of mitotic fidelity in non-neural cells. REST expression and activity is tightly controlled by transcriptional and post-transcriptional mechanisms in a cell and developmental stage-specific manner and perturbations in its levels or function are associated with various pathological states. REST differentially influences target-gene expression through interaction with a wide variety of cellular cofactors in a context-dependent manner. However, the influence of the microenvironment on REST-mediated regulation of gene expression is poorly understood. This review will present our current understanding of REST signaling with a greater focus on its emerging ties with noncoding RNAs and novel interacting partners, as well as its roles in embryonic stem cell self-renewal, cellular plasticity and oncogenesis/tumor suppression.