In soldering of electronic packaging, the research on substituting lead-free solder materials for Pb-Sn alloys has become active due to environmental and health concerns over the use of lead. The reliability of the solder joint is very important in the development of solder materials and it is known that it is related to wettability of the solder over the substrate and microstructural evolution during soldering. It is also highly affected by type and extent of the interfacial reaction between solder and substrate and therefore, it is necessary to understand the interfacial reaction between solder and substrate completely. In order to predict the intermetallic compound (IMC) phase which forms first at the substrate/solder interface during the soldering process, a thermodynamic methodology has been suggested. The activation energy for the nucleation of each IMC phases is represented by a function of the interfacial energy and the driving force for phase formation. From this, it is predicted that the IMC phase with the smallest activation energy forms first. The grain morphology of the IMC at the solder joint is also explained by the calculations which use the energy. The Jackson parameter of the IMC grain with a rough surface is smaller than 2 but it is larger than 2 in the case of faceted grains.