The transcriptional repressor REST has been proposed to target transcription factors crucial for neuronal lineage specification or to maintain pluripotency in embryonic stem (ES) cells, but its specific role in ES cell determination remains unclear. On p. 715, Helle Jørgensen, Amanda Fisher and colleagues report that in ES cells, REST is not required for the repression of transcription factors crucial for neural lineage commitment or for maintaining ES cell potential. By analysing REST-depleted ES cells, the researchers demonstrate that neural determinants,such as MASH1 and neurogenin 1 and 2, remain appropriately repressed, and that the multi-lineage potential and dominant reprogramming capacity of ES cells do not depend on REST. However, a group of genes that is highly enriched for the REST-binding motif RE1, which is implicated in the terminal differentiation and function of neurons, is inappropriately expressed in REST-depleted cells,suggesting that REST might serve to regulate neuronal differentiation programmes rather than the initial stages of neuronal lineage commitment.