The Drosophila Hairy and enhancer of split genes encode basic helix-loop-helix (bHLH) transcriptional repressors that function in the Notch signaling pathway and control segmentation and neural development during embryogenesis. The mammalian homolog of Drosophila Hairy and enhancer of split are the HES gene family members HES1-6, which also encode bHLH transcriptional repressors that regulate myogenesis and neurogenesis. The HES family members form a complex with TLE, the mammalian homolog of groucho, and this interaction is mediated by the carboxy-terminal WRPW motif of the HES proteins. The HES/TLE complex functions by directly binding to DNA instead of interfering with activator proteins. Most HES family members, including HES1 and HES5, preferentially bind to the N box (CACNAG) as opposed to the E box (CANNTG). HES2 binds to both N and E box sites, while HES6 does not bind DNA. Rather, HES6 inhibits HES1 activity, thereby promoting transcription. HES1 and HES2 are expressed in a variety of adult and embryonic tissues.