Although iron is one of the most important metal ions for living organisms, it becomes toxic when in excess or misplaced. This review presents a glance at representative examples of hydroxypyridinone-based chelators, which have been recently developed as potential clinically useful drugs for metal overload diseases, mostly associated with excess of iron but also other hard metal-ions. It also includes a detailed discussion on the factors assisting chelator design strategy toward fulfillment of the most relevant biochemical properties of hydroxypyridinone chelators, highlighting structure-activity relationships and a variety of potential clinical applications, beyond chelatotherapy. This study appears as a response to the growing interest on metal chelation therapy and opens new perspectives of possible applications in future medicine.