Myocardial ischemia is essentially a metabolic event. In this review we will try to distill the essence of a complex series of molecular reactions triggered by the sudden reduction or cessation of blood flow to the heart. We recognize that it is difficult to describe even simple metabolic changes occurring in ischemia without a brief recap of pathways of energy transfer in the normal myocardium. We will therefore begin with a description of the energy substrate supply to a system that is best defined as the heart's remarkable ability for efficient conversion of chemical into mechanical energy. At the core of the system are rates of oxidative phosphorylation of adenosine diphosphate (ADP) that exactly match rates of adenosine triphosphate (ATP) hydrolysis. We will then describe the consequences of a sudden interruption to this balance, namely ischemia. At the same time we will explore metabolic strategies that may be employed to lessen the consequences of ischemia on contractile function, highlighting areas of future research and clinical investigation. The review is not meant to be comprehensive. Its main aim is to discuss the concept of pharmacotherapy as an intervention in altered cellular metabolism, akin to the concept of reperfusion therapy as an intervention in obstructed coronary arteries.