The advent of techniques with the ability to scan massive changes in cellular makeup (genomics, proteomics, etc.) has revealed the compelling need for analytical methods to interpret and make sense of those changes. Computational models built on sound physico-chemical mechanistic basis are unavoidable at the time of integrating, interpreting, and simulating high-throughput experimental data. Another powerful role of computational models is predicting new behavior provided they are adequately validated. Mitochondrial energy transduction has been traditionally studied with thermodynamic models. More recently, kinetic or thermo-kinetic models have been proposed, leading the path toward an understanding of the control and regulation of mitochondrial energy metabolism and its interaction with cytoplasmic and other compartments. In this work, we outline the methods, step-by-step, that should be followed to build a computational model of mitochondrial energetics in isolation or integrated to a network of cellular processes. Depending on the question addressed by the modeler, the methodology explained herein can be applied with different levels of detail, from the mitochondrial energy producing machinery in a network of cellular processes to the dynamics of a single enzyme during its catalytic cycle.