In 1957, they reported the isolation of a Cd(II)-binding protein from horse kidney. (1) Among different animals screened, they chose equine kidney cortex because of its relatively high cadmium content. Incidentally, the same question was posed for zinc 30 years earlier. On the basis of reports in the late 1940s that cadmium is present in various living species, Margoshes and Vallee began to address the question whether cadmium is naturally present for an essential function or as a result of environmental contamination. In the middle of the last century, an ongoing objective was to find biomolecules associated with the metal ions present in biological tissues (“biometals”). We hope that we do due diligence in citing key articles from a wide community of scientists whose disciplines have been and will be impacted by the fundamental roles of MTs. By necessity, a scientific literature with over 20 000 original articles, numerous reviews, books, and conference proceedings will have to be reduced to ∼2% with representative articles. It will then address two significant developments that challenged the general perception about their structure, chemical reactivity, and metal complexation, proceed to discuss how the chemical properties of MTs are limited by the biological environment and how the highly dynamic properties of MTs relate to our current knowledge in mammalian metal biochemistry, and finally attempt a synthesis of our knowledge with the goal of advancing the understanding of their functions. The article will start with the discovery of metallothioneins and definitions of the term with an account of the first 40 years of MT research culminating in the determination of three-dimensional (3D) structures of mammalian MTs. Seen with this perspective, the search for a function of an entire family of proteins turns out to be a quite educational lesson in the history of science. MT is emblematic of the difficulties faced when trying to define functions of proteins without known activities. Resolutions of conjectures had to await additional discoveries, especially insights into the molecular basis of how cellular metal metabolism is controlled. Trials and tribulations emerged from some assumptions in lieu of facts and from not interpreting chemistry in the context of biology. In a discussion of discoveries seriatim, the etymology of “metallothionein” and the epistemology of the field will foster an understanding of how our present ideas about metallothionein (MT) were shaped. It is crucial to start the narration with the early history to understand the facts and why and how contentions developed. Three human generations have witnessed the development of the field of metallothioneins. Recent advances in understanding the control of cellular zinc and copper homeostasis are the foundation for suggesting that mammalian metallothioneins provide a highly dynamic, regulated, and uniquely biological metal buffer to control the availability, fluctuations, and signaling transients of the most competitive Zn(II) and Cu(I) ions in cellular space and time. Many fundamental signal transduction pathways regulate the expression of the dozen of human metallothionein genes. Their coordination dynamics allows a vast conformational landscape for interactions with other proteins and ligands. The proteins, therefore, also exist in different redox states of the sulfur donor ligands. It endows the proteins with redox activity and a specific pH dependence of their metal affinities. The homoleptic thiolate coordination of mammalian metallothioneins is important for their molecular mechanism. They exist in multiple forms with different degrees of metalation and types of metal ions. The proteins need to be seen in their biological context, which limits and defines the chemistry possible. The terms metallothionein and thionein are ambiguous and insufficient to understand biological function. It challenges the dogma that the biologically relevant structure of the mammalian proteins is only the one determined by X-ray diffraction and NMR spectroscopy. This article guides through the history of investigations and resolves multiple contentions by providing new interpretations of the structure-stability-function relationship. The functions, purposes, and roles of metallothioneins have been the subject of speculations since the discovery of the protein over 60 years ago.