While impressive solid oxide fuel cell (SOFC) performance has been achieved, durability under “real world” conditions is still an issue for commercial deployment. In particular cathode exposure to H2O and CO2 can result in long-term performance degradation issues. Therefore, we have embarked on a multi-faceted fundamental investigation of the effect of these contaminants on cathode degradation mechanisms in order to establish cathode composition/structures and operational conditions to enhance cathode durability. Using a Focused Ion Beam (FIB)/SEM we are quantifying in 3-D the microstructural changes of the cathode before and after the onset of cathode performance degradation. This includes changes in TPB density, phase-connectivity, and tortuosity, as well as tertiary phase formation. This is then linked to heterogeneous catalysis methods to elucidate the cathode oxygen reduction reaction (ORR) mechanism to determine how H2O and CO2 affect the ORR as a function of temperature, time, and composition. By use of in-situ 18O-isotope exchange of labeled contaminants we are investigating whether oxygen incorporated in the lattice of LSM and LSCF, and their composites with YSZ and GDC, respectively, originated from ambient O2 or the contaminant, as well as intermediate adsorbed species and mechanisms that lead to degradation. The results will be used to develop a cohesive and overarching theory that explains the microstructural and compositional cathode performance degradation mechanisms.