The Notch signaling pathway is important for cell-cell communication, which involve gene regulation mechanisms that control multiple cell differentiation processes during embryonic and adult life. It critically influences cell proliferation, differentiation, and apoptosis in metazoans. The hairy and enhancer of split (HES) family is a basic helix-loop-helix (bHLH) type trancriptional repressor and acts as Notch effectors by negatively regulating expression of downstream target genes such as tissue-specific transcription factors. HES-1 is an upstream negative regulator of REST expression. Silencing of the transcriptional repressor REST is required for terminal differentiation of neuronal and β-cells. Recent integrative genomic analyses on HES/HEY family suggest that HES1 and HES3 are target genes of the embryonic stem cell-specific network of transcription factors, and that HES1, HES5, HEY1, HEY2 and HEYL are target genes of Notch signaling pathway.