The helix-loop-helix (HLH) family of transcriptional regulatory proteins are key players in a wide array of developmental processes. Over 240 HLH proteins have been identified to date in organisms ranging from the yeast Saccharomyces cerevisiae to humans (6). Studies in Xenopus laevis, Drosophila melanogaster, and mice have convincingly demonstrated that HLH proteins are intimately involved in developmental events such as cellular differentiation, lineage commitment, and sex determination. In yeast, HLH proteins regulate several important metabolic pathways, including phosphate uptake and phospholipid biosynthesis (19, 67, 112). In multicellular organisms, HLH factors are required for a multitude of important developmental processes, including neurogenesis, myogenesis, hematopoiesis, and pancreatic development (12, 86, 127, 179). The purpose of this review is to examine the structure and functional properties of HLH proteins.