As young students of materials science and engineering we learn about the differences between pearlite and martensite—the take away—microstructure influences material response. This is such a central concept to our field that we often take it for granted. Despite a century (or more) of carefully studying links between processing, structure and performance, when materials are introduced to extremely harsh conditions our fundamental understanding is challenged to predict the outcome. Extreme conditions may range from the combustion zone of a gas turbine engine, to the reactor core of a nuclear plant, to a very small cantilever in a MEMS device or a high performance battery that must survive countless cycling events, the list could go on and on. In this talk we will discuss several short case studies in which developing a fundamental understanding between local microstructural evolution, thermodynamic and kinetic driving forces and mechanical response provides unique avenues to improve the overall durability or longevity of these materials under extreme conditions.