This chapter presents the main etiologies of vitamin B12 deficiency in relation to different steps of the cobalamin transport and metabolism. Vitamin B12 is produced exclusively by microbial synthesis in the digestive tract of animals. Vitamin B12 deficiency caused by limited intake of vitamin dietary sources is rare, even exceptional, in general population. The intestinal absorption of cobalamin into the enterocytes takes place in the terminal ileum via intrinsic factor receptor cubilin. In adults, vitamin B12 deficiency is classically caused by A. M. Biermer's also named Thomas Addison's disease, formerly known as pernicious anemia. Several disorders commonly seen in gastroenterology practice might be associated with cobalamin malabsorption. Patients affected with the rare autosomal recessive disorders display severe malformations with proteinuria. The clinical manifestations of the metabolic abnormalities are hereditary megaloblastic anemia, neurological defects, malformations, increased cardiovascular thrombotic risk and renal disease, and methylmalonic acidemia.