Pernicious anemia (PA) is a serious form of vitamin B12-defciency. Vitamin B12 belongs together with heme and chlorophyll to the tetrapyrrole family (Figure 1) (Yin and Bauer 2013). Vitamin B12 is an evolutionarily ancient (≈ 3.8 x 109 years old) cofactor that was responsible for energy production through fermentation of small organic molecules in the absence of exogenous electron acceptors in the prokaryotic anaerobic world (Figure 2) (Santander et al. 1997). In the course of evolution siroheme later allowed making use of inorganic electron acceptors, before oxygen production by chlorophyll made aerobic respiration through heme possible. Almost 1% of the genome of S. typhymurium is dedicated to vitamin B12 synthesis and transport (Roth et al. 1996). Though being one of the structurally most complex, non-polymeric biomolecules synthesized by nature ,eukaryotic organisms do not produce B12 (Figure 2). As a consequence, this vitamin is essential for human metabolism, albeit only required in trace amounts (possibly as low as 1 μg/d, while the recommended daily allowances in adults are 2.4 μg/d) and functions as cofactor in only two enzymes, methionine synthase and (R)-methylmalonyl-CoA mutase (Helliwell et al. 2011). The remarkable discovery of vitamin B12 was only possible and proceeded by the endeavor to fnd effective treatment options for PA, one of the conditions causing severe vitamin B12-deficiency. The scientific progress was, however, slow and stretched over a period of almost 200 years from the frst description of PA, to the evolution of theories about possible causes and ultimately the invention of effective treatments.