The basic/helix-loop-helix (bHLH) proteins are a superfamily of transcription factors that have been well characterized in nonplant eukaryotes, especially in mammalian systems, in which considerable structural, functional, and phylogenetic analyses have been performed. The data indicate that bHLH proteins are important regulatory components in transcriptional networks in these systems, controlling a diversity of processes from cell proliferation to cell lineage establishment.This family is defined by the bHLH signature domain, which consists of 60 amino acids with two functionally distinct regions. The basic region, located at the N-terminal end of the domain, is involved in DNA binding and consists of 15 amino acids with a high number of basic residues. The HLH region, at the C-terminal end, functions as a dimerization domain and is constituted mainly of hydrophobic residues that form two amphipathic -helices separated by a loop region of variable sequence and length. Outside of the conserved bHLH domain, these proteins exhibit considerable sequence divergence. Cocrystal structural analysis has shown that the interaction between the HLH regions of two separate polypeptides leads to the formation of homodimers and/or heterodimers and that the basic region of each partner binds to half of the DNA recognition sequence. Some bHLH proteins form homodimers or restrict their heterodimerization activity to closely related members of the family. On the other hand, some can form heterodimers with one or several different partners.