Iron plays an essential role in all living cells because of its unique chemical properties. It is also the most abundant trace element in mammals. However, when iron is present in excess or inappropriately located, it becomes toxic. Excess iron can become involved in free radical formation, resulting in oxidative stress and cellular damage. Iron chelators are used to treat serious pathological disorders associated with systemic iron overload. Hydroxypyridinones stand out for their outstanding chelation properties, including high selectivity for Fe in the biological environment, ease of derivatization, and good biocompatibility. Herein, we overview the potential for multifunctional hydroxypyridinone-based chelators to be used as therapeutic agents against a wide range of diseases associated either with systemic or local elevated iron levels.