This chapter will introduce the in-reactor behavior of oxide fuels (UO2 and MOX) in both light water reactors and fast breeder reactor (FBR). As another example, the behavior of metallic fuels in FRs will be briefly addressed too. For these different kinds of fuels, the general features of the nuclear fuel behavior related to the severe high-temperature and irradiation conditions will be presented. Then the effect of these extreme conditions on the fuel microstructure evolution will be explained as well as the consequences on the evolution of the fuel chemical composition related to the fission product formation. Transport phenomena due to thermal and chemical gradient will be addressed too. Finally, a description of the fuel–cladding chemical interaction that can lead to the cladding corrosion will be introduced.