Nuclear fuel has a much higher energy density compared to conventional fuels like fossil and allows an almost green house emission free energy production. Despite its inherent advantages, the performance of nuclear fuel has to be amended due to economical as well as ecological reasons, without constricting its safe use. A higher performance of nuclear fuel means extracting more energy from the fuel. The higher energy yield also implies less volume of highly radioactive spent fuel per produced energy unit. The stronger energy extraction from nuclear fuel leads to a higher burn-up, which means pushing the limits, with the safety limitations fixed by the regulators. This has been carried out, for instance, in Switzerland for many years and has reached about 80 MW d kg−1 or about 8% of fission per initial metal atom “FIMA” in generation (GEN) II reactors. Nuclear fuels consist of different constituents which are the matrix, e.g. non-inert or inert, a fissile part, components such as burnable poisons, fertile isotopes or grain enlargers. The fuel matrix is currently described as the first barrier between fission products and the next nuclear barrier towards the environment. It must remain effective over years. The higher the burn-up the higher the concentration of fission products is in the fuel matrix. The fissile part in the fuel directly contributes to the energy production. The typical enrichment of fissile isotopes in a commercial nuclear fuel is around 5%. A higher enrichment followed by a respective higher burn-up may affect the fission product retention capability of the fuel matrix and its interaction with the cladding. The doping with grain enlargers leads to bigger fuel grains, implying longer diffusion paths, retaining gaseous fission products in the matrix under certain temperature conditions. This shall allow a better pressure control at higher burn-up in GEN II and III reactors. To reach very high burn up >100 MW d kg−1 (equivalent), the only possibilities are offered by inert matrix fuels. This is investigated in the last part of this study. The zirconia inert matrix concept could be used in a last cycle e.g. to burn plutonium excess and minor actinides prior to geological disposal. Prior to and after burn-up, the fuel material is characterized by micro- or nano-beam analysis to gain information on the dispersity of the system, the presence of defect and segregated phases as well as to track fission products. These studies can be performed through a multiscale approach. The fuel structure can be revealed at the macro-, micro-, nano- and sub-nano-level.