The Mi-2/NuRD chromatin remodeling complex links multiple transcriptional regulatory processes including histone deacetylation, histone demethylation, nucleosome mobilization and recruitment of other regulatory proteins. In some contexts, Mi-2/NuRD functions as a barrier to transcriptional activation by working in opposition to other chromatin remodelers such as SWI/SNF. Alternatively, the Mi-2beta ATPase subunit of Mi-2/NuRD can promote transcription. Together, these gatekeeper functions of Mi-2/NuRD influence cell fate decisions by modulating transcriptional activity. Recent studies have shown the importance of Mi-2/NuRD both in maintaining hematopoietic stem cell (HSC) pools and in normal lineage progression. Furthermore, components of Mi-2/NuRD complexes are modular co-repressors/co-activators comprising multiple protein subunits that have been linked directly to oncogenesis and have potential as therapeutic targets for cancer treatment. Mi-2/NuRD's essential functions in metazoan cell fates and activities underscore its importance as a focal point of epigenetic research.