Cardiotoxicity represents a significant adverse effect associated with various therapeutic interventions and the misuse of substances, profoundly disrupting cardiac bioenergetics. This chapter examines the underlying mechanisms of cardiotoxicity, emphasizing the roles of mitochondrial dysfunction and oxidative stress, which are instrumental in mediating effects on cardiac metabolism and ATP synthesis. We investigate how various pharmacological agents, including anthracyclines and HER2-targeted therapies, in addition to radiation exposure and the consumption of recreational drugs, induce oxidative stress and compromise mitochondrial integrity. Notably, anthracyclines, such as doxorubicin, cause mitochondrial dysfunction by promoting the generation of excessive reactive oxygen species (ROS). In parallel, HER2-targeted therapies disrupt the AKT signaling pathway, resulting in significant metabolic dysregulation. Moreover, radiation-induced cardiotoxicity is characterized by alterations in DNA integrity, mitochondrial impairment, and modifications in protein expression, all leading to compromised cardiac function. Additional classes of drugs, including antipsychotic medications, antibiotics, and anti-retroviral agents, have been implicated in cardiotoxicity through mechanisms such as the inhibition of mitochondrial protein synthesis and disturbances in energetic homeostasis. Furthermore, chronic alcohol consumption exacerbates oxidative stress and mitochondrial impairment, contributing to the development of alcoholic cardiomyopathy. Overall, these various cardiotoxic agents converge on mitochondrial dysfunction, highlighting the urgent need for targeted strategies aimed at mitigating their detrimental effects on cardiac energetics, optimizing therapeutic effectiveness, and ultimately preventing heart failure.