Transcobalamin II (TC II), a nonglycoprotein secretory protein of molecular mass 43 kDa, and its plasma membrane receptor (TC II-R), a heavily glycosylated protein with a monomeric molecular mass of 62 kDa, are essential components of plasma cobalamin (Cbl; vitamin B12) transport to all cells. Evidence from studies over the past 10 years has provided some important information on their structure, regulation of expression, and function. Some of the specific findings include (a) identification of the structural relationship of the ligand TC II with other members of the Cbl-binding family of proteins, intrinsic factor (IF) and haptocorrin (HC), (b) regulation of TC II gene expression, (c) molecular basis for human TC II deficiency in patients with a lack of plasma TC II, (d) membrane expression, interactions, and dimerization of TC II-R, and (e) targeting and function of TC II-R in polarized epithelial cells. It is hoped that some of the recent findings presented in this review will provide new insights into the structure and function of these two fascinating proteins and stimulate future research in this area.