Vitamin B12 (cobalamin) deficiency and its related hematological and neurological manifestations, of which pernicious and megaloblastic anemia are the most recognized entities, have puzzled the medical community for over a century. These conditions are described in all ages, race and ethnicities, continents, and socioeconomic groups. Among the etiologies identified in vitamin B12 deficiency, nutritional deficiency, including restrictive diets due to access to appropriate food items, food or oral aversion, or personal choice, is recognized in developed and developing countries. Other etiologies include inherited or genetic defect in the metabolism of vitamin B12, immune-mediated, or absorption-related defects. Understanding the pathophysiology of this phenomenon has allowed us to provide the adequate treatment to reverse the changes in the affected systems successfully.