The understanding of the role of vanadium enzymes and of vanadium compounds (VCs) in biology, as well as the design of new vanadium-based species for catalysis, materials science and medicinal chemistry has exponentially increased during the last decades. In biological systems, VCs may rapidly interconvert under physiological conditions and several V-containing moieties may be formed and bind to proteins. These interactions play key roles in the form transported in blood, in the uptake by cells, in inhibition properties and mechanism of action of essential and pharmacologically active V species. In this review, we focus on the recent advances made, namely in the application of the theoretical methodologies that allowed the description of the coordinative and non-covalent VC–protein interactions. The text is organized in six main topics: a general overview of the most important experimental and computational techniques useful to study these systems, a discussion on the nature of binding process, the recent advances on the comprehension of the V-containing natural and artificial enzymes, the interaction of mononuclear VCs with blood and other physiologically relevant proteins, the binding of polyoxidovanadates(V) to proteins and, finally, the biological and therapeutic implications of the interaction of pharmacologically relevant VCs with proteins and enzymes. Recent developments on vanadium-containing nitrogenases, haloperoxidases and nitrate reductases, and binding of VCs to transferrin, albumins, immunoglobulins, hemoglobin, lysozyme, myoglobin, ubiquitin and cytochrome c are discussed. Challenges and ideas about desirable features and potential drawbacks of VCs in biology and medicine and future directions to explore this chemistry area are also presented. The deeper understanding of the interactions of V-species with proteins, and the discussed data may provide the basis to undertake the investigation, design and development of new potentially active VCs with a more solid knowledge to predict their binding to biological receptors at a molecular point of view.