eIF2B (eukaryotic initiation factor 2B) is a multisubunit protein that is required for protein synthesis initiation and its regulation in all eukaryotic cells. Mutations in eIF2B have also recently been found to cause a fatal human disease called CACH (childhood ataxia with central nervous system hypomyelination) or VWM (vanishing white matter disease). This review provides a general background to translation initiation and mechanisms known to control eIF2B function, before describing molecular genetic and biochemical analysis of eIF2B structure and function, integrating work from studies of the yeast and mammalian eIF2B proteins.