The article reviews the mechanisms underlying acute protection from cardiac ischemia-reperfusion injury, focusing on the role of mitochondria. During ischemia, ATP depletion and increased calcium (Ca²⁺) levels lead to mitochondrial Ca²⁺ accumulation and increased reactive oxygen species (ROS), which can open the mitochondrial permeability transition pore (MPTP) and cause cell death. Preconditioning and postconditioning activate signaling pathways that reduce Ca²⁺ overload and ROS, thereby protecting against ischemic injury. The review discusses the relative roles of ischemia and reperfusion in irreversible injury, the involvement of apoptosis, necrosis, and autophagy, and the mechanisms by which cardioprotective signals target mitochondria. It highlights the importance of reducing Ca²⁺ overload and ROS in preventing cell death and the potential of targeting these pathways for therapeutic intervention.The article reviews the mechanisms underlying acute protection from cardiac ischemia-reperfusion injury, focusing on the role of mitochondria. During ischemia, ATP depletion and increased calcium (Ca²⁺) levels lead to mitochondrial Ca²⁺ accumulation and increased reactive oxygen species (ROS), which can open the mitochondrial permeability transition pore (MPTP) and cause cell death. Preconditioning and postconditioning activate signaling pathways that reduce Ca²⁺ overload and ROS, thereby protecting against ischemic injury. The review discusses the relative roles of ischemia and reperfusion in irreversible injury, the involvement of apoptosis, necrosis, and autophagy, and the mechanisms by which cardioprotective signals target mitochondria. It highlights the importance of reducing Ca²⁺ overload and ROS in preventing cell death and the potential of targeting these pathways for therapeutic intervention.