The introduction of metal complexes as therapeutic or diagnostic agents in chemical biology has led to the largely growing field of metals in medicine. Most notably, the utilization of cis-[Pt(NH3)2Cl2], or cisplatin, as an anticancer drug agent has inspired a wide variety of metal-based therapeutics and diagnostics. Alternatively, researchers have investigated the use of metal complexes as cytoprotective agents, as opposed to anticancer cytotoxic agents. One such biological process that can take advantage of this utilization of metal complexes is mitochondrial calcium (mCa2+) overload, a phenomenon linked to a variety of diseases and disorders, including ischemia-reperfusion injury (IRI). Chapter 1 of this dissertation is a detailed review of metal-based complexes that have provided protective effects against IRI through a variety of mechanisms. We will then more thoroughly examine the chemical inhibition of the mitochondrial calcium uniporter (MCU), a transmembrane protein responsible for shuttling cytosolic Ca2+ into the mitochondrial matrix. Specifically, the dinuclear metal complexes Ru265 and Os245 will be discussed as potent, cell-permeable inhibitors of the MCU.Chapter 2 will discuss the activation of Ru265 through the process of aquation via ligand substitution with alkyl carboxylate ligands. This process demonstrates a viable strategy to inhibit the MCU over time. Chapter 3 expands upon this strategy by employing adamantane-carboxylate as a ligand for Ru265 and Os245. These complexes demonstrate host/guest chemistry with the supramolecular compound cucurbit-[7]-uril, presenting the ability for the supramolecular delivery of these complexes. Finally, in chapter 4, we examine a different metal center in cobalt. Caged ligands around a Co(III) center have been widely reported in literature, but their biological activity has not yet been explored. We look at these complexes as MCU inhibitors and discover that one such compound is potent and cell-permeable, providing a cheaper alternative to Ru265 and Os245 to study mCa2+ dynamics. Collectively, these studies demonstrate that chemical modifications can increase the availability of these metal-complexes as MCU-inhibitors.