The up-and-down beta-barrel is a common folding motif found frequently in proteins that bind and transport hydrophobic ligands. It is formed by an array of beta-strands arranged in an antiparallel manner with each strand hydrogen-bonded to neighboring strands nearly always adjacent in the amino acid sequence. The arrangement is completed by forming hydrogen bonds between the first and last strands. The barrel motif so formed produces interior and exterior components. Proteins belonging to this class of up-and-down beta-barrels are found typically to be lipid-binding proteins in which the interior surface forms a cavity or pit that serves as the ligand binding region. Two evolutionarily distinct but structurally related families of such carriers have been identified by comparing known crystal structures. One group found intracellularly uses a 10-stranded beta-structure and a second family of proteins typically found extracellularly utilizes an 8-stranded motif. The 10-stranded beta-barrels have a large, hydrophilic water-filled interior cavity that serves as the ligand-binding domain. Hydrophobic lipids such as fatty acids and retinoids bind within the cavity, totally sequestered from the external milieu. The 8-stranded beta-barrel proteins have a hydrophobic pit, which serves as the ligand-binding domain for compounds such as bilins and retinoids. The up-and-down beta-barrel motif appears to be one of nature's primary choices for hydrophobic ligand transport proteins.