Mitochondrial calcium levels play an important role in regulating physiological processes. Accordingly, dysregulation of mitochondrial calcium levels, particularly in the form of mitochondrial calcium overload, can trigger cell death. This phenomenon has been implicated in many different pathological conditions like heart disease and stroke. In this presentation, we describe our efforts to develop and understand ruthenium- and osmium-based mitochondrial calcium uptake inhibitors as potential therapeutic tools for preventing mitochondrial calcium overload. This research builds upon the discovery of the dinuclear nitrido-bridged compound Ru265. New analogues, including the osmium analogue Os245, are described with an emphasis on understanding their mechanisms of activation. In addition, analogues with dual functionality will also be presented. Lastly, the limitations and future challenges associated with these compounds will be discussed.