The differentiation of pluripotent embryonic stem cells is regulated by networks of activating and repressing transcription factors that orchestrate determinate patterns of gene expression. With the recent mapping of target sites for many transcription factors, it has been a conundrum that so few of the genes directly targeted by these factors are transcriptionally responsive to the binding of that factor. To address this, we generated genome-wide maps of the transcriptional repressor REST and five of its corepressors in mouse embryonic stem cells. Combining these binding-site maps with comprehensive gene-expression profiling, we show that REST is functionally heterogeneous. Approximately half of its binding sites apparently are nonfunctional, having weaker binding of REST and low recruitment of corepressors. In contrast, the other sites strongly recruit REST and corepressor complexes with varying numbers of components. Strikingly, the latter sites account for almost all observed gene regulation. These data support a model where productive gene repression by REST requires assembly of a multimeric "repressosome" complex, whereas weak recruitment of REST and its cofactors is insufficient to repress gene expression.