Inhibitor of DNA-binding/differentiation proteins, also known as ID proteins comprise a family of proteins that heterodimerize with basic helix-loop-helix (bHLH) transcription factors to inhibit DNA binding of bHLH proteins. ID proteins also contain the HLH-dimerization domain but lack the basic DNA-binding domain and thus regulate bHLH transcription factors when they heterodimerize with bHLH proteins. The first helix-loop-helix proteins identified were named E-proteins because they bind to Ephrussi-box (E-box) sequences. In normal development, E proteins form dimers with other bHLH transcription factors, allowing transcription to occur. However, in cancerous phenotypes, ID proteins can regulate transcription by binding E proteins, so no dimers can be formed and transcription is inactive. E proteins are members of the class I bHLH family and form dimers with bHLH proteins from class II to regulate transcription. Four ID proteins exist in humans: ID1, ID2, ID3, and ID4. The ID homologue gene in Drosophila is called extramacrochaetae (EMC) and encodes a transcription factor of the helix-loop-helix family that lacks a DNA binding domain. EMC regulates cell proliferation, formation of organs like the midgut, and wing development. ID proteins could be potential targets for systemic cancer therapies without inhibiting the functioning of most normal cells because they are highly expressed in embryonic stem cells, but not in differentiated adult cells. Evidence suggests that ID proteins are overexpressed in many types of cancer. For example, ID1 is overexpressed in pancreatic, breast, and prostate cancers. ID2 is upregulated in neuroblastoma, Ewing’s sarcoma, and squamous cell carcinoma of the head and neck. Function ID proteins are key regulators of development where they function to prevent premature differentiation of stem cells. By inhibiting the formation of E-protein dimers that promote differentiation, ID proteins can regulate the timing of differentiation of stem cells during development. An increase in ID expression is seen in embryonic and adult stem cells. ID proteins also promote cell cycle progression, delaying senescence, and help facilitate cell migration. In contrast, inappropriate regulation of ID proteins in differentiated cells can contribute to tumorigenesis. Generally, IDs function as oncogenes. When ID proteins are overexpressed, cell proliferation is enhanced and cells become insensitive to growth factor depletion. Expression of ID proteins in neurons halts neuron axon growth and allows elongation of neurons. Knockout mouse data show that ID genes are essential for heart development. There is some controversy surrounding the ID proteins and their role in cancer, but overexpression is seen in