Pt(II)-based agents are used in approximately 50% of all cancers that are treated with chemotherapy. Unfortunately, the dose-limiting toxicity of these agents remains problematic for patients undergoing treatment. Additionally, Pt(II) therapeutics suffer from transporter-dependent uptake, limited chemical functionalization, and high susceptibility to inactivation by free thiols within the cytosol. Developing small molecules with non-canonical mechanisms of action is one strategy that can be employed to circumvent these limitations. Utilization of coordination complexes with Ru(II) metal centers is one attractive strategy. Ru(II) compounds are often octahedral, facilitating greater accessibility for chemical diversity; Ru(II) complexes use passive transport and transferrin-mediated transport for cellular uptake; Ru(II) is a harder Lewis acid than Pt(II), facilitating reduced thiol coordination, which results in reduced inactivation. Herein, we investigate several Ru(II) scaffolds that display non-canonical mechanisms. They are able to preferentially induce ribosome biogenesis stress and mitochondrial membrane uncoupling. Complementary to this work, we investigated the mechanism of action for photoactive chemotherapeutics (PACTs) and photodynamic therapeutics (PDTs). Despite the fact that reactive oxygen species (ROS) generated by PDTs can oxidize nucleobases, cellular bioenergetic pathways are effectively shut down before DNA damage could be recognized by DNA damage repair (DDR) machinery, suggesting that, unlike Pt(II) therapeutics, DNA damage is not the cause of cell death for these compounds.