After 40 years of significant work, it was generally accepted that chromium in its trivalent valence state, Cr(III), is an essential micronutrient for humans. This view began to be challenged around the turn of the millennium. Some investigators argue that its effects on glucose and lipid metabolism reflect a pharmacological rather than a nutritional mode of action while yet others express concern about the toxicity and safety of supplemental chromium. Understanding the conjectures requires a reflection on the different definitions of “essential” and a perspective on the development of the field, which in itself is a remarkable snippet of science history and education. At the center of the discussion is our failure to have established a molecular structure and a specific site of action of a biological chromium complex. Instead, many different types of Cr(III) complexes, in particular chromium picolinate, but also those with nicotinate, propionate, histidinate, chloride, and other ligands, all with different chemical properties and biological activities, are being used in laboratory investigations and supplementation. Without knowledge of the metabolic transformations and the specific chemical properties that biological ligands impart on chromium, many of these investigations, in particular those ex vivo, have limited value for understanding chromium’s biological function. Whether a chromium deficiency exists in humans and who is affected is poorly defined. There is evidence for the efficacy of chromium supplements in improving conditions in metabolic syndrome and in some diabetes Type 2 patients, but there are no effects on body composition in healthy individuals. Chromium is present in human tissues and in our food and Cr(III) compounds are given in (total) parenteral nutrition, taken as a supplement by athletes and bodybuilders, are ingredients of vitamin pills consumed by the general population, and are employed in animal nutrition. Another contentious issue is whether Cr(III) complexes are safe, as chromium in its hexavalent state, Cr(VI) (chromate), is genotoxic and a group I carcinogen for humans with sufficient evidence for inhalation and lung cancer. For the benefit of human health, there is a continuing need for a balanced view and informed and robust experiments to determine the specific biological molecules that are involved in the metabolism of Cr(III), the activity of biological Cr(III) complexes at specific sites of action, and the amount of supplemental Cr(III) that potentially causes long-term toxicity.