One major mechanism for achieving cell-type-specific functions in somatic cells is the differential usage of stage-and tissue-specific genes. This is in large part regulated by transcription factors that interact directly with DNA elements controlling transcription of these genes. Several groups of transcription factors with key roles in cellular differentiation and function have been characterized, and the list of transactivating proteins with crucial functions in vivo is continuously growing. One group of evolutionarily conserved proteins with defined roles in a large variety of species are the basic helixloop-helix (bHLH) proteins (42, 44). These factors are involved in a large number of differentiation processes, including such diverse events as sex determination in Drosophila melanogaster and B-lymphopoiesis in mice (9, 15, 38, 42, 48). In 1993, two independent reports presented a novel type of HLH protein with a dimerization domain containing two helices with homology to the second helix of the classical bHLH protein dimerization domain, but with a different type of DNA binding domain (DBD). This factor was cloned both in a Saccharomyces cerevisiae one-hybrid experiment designed to identify factors interacting with the olfactory-restricted olfactory marker protein-1 (OMP-1) promoter (69), and by biochemical purification of a factor interacting with the B-lymphocyte-restricted mb-1 promoter (27). It was accordingly named Olf-1, or early B-cell factor (EBF), which in turn led to the designation of the factor as O/E-1. Later reports showed that mice expressed at least three more members of this family, EBF2 (mMot1/O/E-3), EBF3 (O/E-2)(23, 40, 71), and O/E-4 (70), with a high degree of similarity in the DNA-binding and dimerization domains. Isolation of the O/E homologue Collier from D. melanogaster (12) provided a proof of principle for the existence of a new family of evolutionarily conserved proteins, and family members have now been cloned in several species (7, 17, 24, 27, 46, 52, 69)(Table 1). The biological roles of this protein family are beginning to be unraveled, and here we are compiling some of the available information about the roles of Collier/Olf/EBF (COE) proteins to give an overview of the known functions of this protein family in specific model systems and in different model species.