New boundary conditions are foreseen which require alternative lead-free solder materials to Pb-Sn alloys in soldering of electronic packaging due to increasing environmental and health concerns over the use of lead. The reliability of soldered devices is related to wettability of the solder to the substrate and to microstructural evolution of the joint during soldering operation or in use. The reliability of the solder joint is strongly affected by type and extent of the interfacial reaction between solders and substrates. Accordingly, the solder-substrate interaction is increasingly important and a deeper understanding of the interfacial reaction between solder and substrate is necessary. A thermodynamic methodology to predict the intermetallic compound (IMC) phase, which forms first at the substrate/solder interface during the soldering process, has been suggested. By comparing the activation energy for nucleation of individual IMC phases, which is a function of the interfacial energy and the driving force for formation, the IMC phase that forms first is predicted as the one with the smallest activation energy. Additionally, the grain morphology of IMC at the solder joint has been explained through the energy-based calculations. The Jackson's parameter of the IMC grain with a rough surface is smaller than 2 while it is larger than 2 for faceted grains.