HES1 (hairy and enhancer of split 1) is a basic helix-loop-helix (bHLH) transcriptional repressor that serves as a mammalian homolog of the Drosophila Hairy and Enhancer of split proteins and functions as a canonical downstream target of Notch signaling. It represses genes that require bHLH proteins for their transcription, and unlike most bHLH factors that bind E-box motifs, HES1 preferentially recognizes N-box elements (CACNAG) through a unique proline residue in its basic domain. Its repressor activity depends on three conserved domains: the bHLH region, a central Orange domain, and a C-terminal WRPW motif that mediates interaction with the Groucho/TLE corepressor. Functionally, HES1 is expressed at high levels in undifferentiated neural precursor cells and its expression declines upon differentiation, where it regulates cell fate decisions by antagonizing proneural bHLH proteins such as Mash1 and inhibiting MyoD1 and ASH1 to suppress myogenesis.