Since the early 40s when the first research related to the development of the atomic bomb began for the Manhattan Project, actinides (An) and their association with the use of nuclear energy for civil applications, such as in the generation of electricity, have been a constant source of interest and fear. In 1962, the first Society of Toxicology (SOT), led by H. Hodge, was established at the University of Rochester (USA). It was commissioned as part of the Manhattan Project to assess the impact of nuclear weapons production on workers’ health. As a result of this initiative, the retention and excretion rates of radioactive heavy metals, their physiological impact in the event of acute exposure and their main biological targets were assessed. In this context, the scientific community began to focus on the role of proteins in the transportation and accumulation of An. The first studies focused on the identification of these proteins. Thereafter, the continuous development of physico-chemical characterization techniques has made it possible to go further and specify the modes of interaction with proteins from both a thermodynamic and structural point of view, as well as from the point of view of their biological activity. This article reviews the work performed in this area since the Manhattan Project. It is divided into three parts: first, the identification of the most affine proteins; second, the study of the affinity and structure of protein-An complexes; and third, the impact of actinide ligation on protein conformation and function.