The effect of several metallurgical variables on the thermal fatigue behavior of high-temperature materials systems was studied using a highly characterized high-velocity hot gas stream to produce a well-defined strain/temperature/time cycle. Metallurgical factors considered were: alloy compositions in both cast cobalt- and nickel-base superalloys, degree of microstructural refinement, grain orientation, effect of presence and morphology of carbides, surface/environmental interaction (surface stability), and protective coatings. The nickel-base alloys studied were superior or equivalent to the cobalt-base alloys when compared on uncoated and coated bases. Within a given alloy class the effect of alloy chemistry as it affects oxidation behavior was shown to be significant. On polycrystalline substrates, an inward type of diffusion aluminide coating improved fatigue performance, whereas an outward type was detrimental. “Overlay” coatings show a great deal of potential in providing an optimum in mechanical/protective response. Columnar-grained alloys when strained along the growth direction gave fatigue resistance superior to their polycrystalline counterparts. The importance of recognizing the unique compositional/microstructural/mechanical nature of a coating in achieving optimum thermal fatigue resistance for high-temperature materials systems is emphasized.