The impact of microstructure on the reaction kinetics during heating of high energy ball milled powders was investigated, using an AI-Ni powder as a typical ductile-ductile system and Al-TiO2 powder as a typical ductile-brittle system. It was found that with increasing milling time the microstructure of the AI-Ni system developed from Ni particles entrapped in Al matrix structure to Al/Ni multilayer structure; while the microstructure of the Al-TiO2 system retained the TiO2 particles entrapped in Al matrix structure. Upon subsequent heating, noticeable reactions occurred only after the melting of the Al rich phase in the entrapped particle structures in both AI-Ni and AlTiO2 systems, while low temperature reactions occurred in the Al/Ni multi-layer structure. The reaction between Al and TiO2 occurred in two stages with different mechanisms. The first noticeable reaction between Al and TiO2 occurred when Al started melting, forming Al3Ti and Al2O3 The formation of solid Al3Ti and Al2O3 hindered the reaction between molten Al and solid TiO2. Further reaction between Al and TiO2 only occurred at higher temperatures and the process is likely to be controlled by the diffusion through the solid Al3Ti and Al2O3.