In the design of exhaust manifolds for internal combustion engines the materials used must exhibit resistance to corrosion at high temperatures while maintaining a stable microstructure. Cast iron has been used for manifolds for many years by auto manufacturers due to a combination of suitable mechanical properties, low cost, and ease of casting. Over time cast iron is susceptible to microstructural changes, corrosion, and oxidation which can result in failure due to fatigue. This thesis seeks to answer the question: “Can observed microstructural changes and measured high temperature fatigue life in cast iron alloys be used to develop a predictive model for fatigue life?” the importance of this question lies in the fact that there is little data for the behavior of cast iron alloys at high temperature. For this study two different types of cast iron, 50HS and HSM will be examined. Of particular concern for the high Si+C cast irons (and Mo in the case of the HSM cast iron) are subsurface microstructural changes that result due to heat treatment including (1) decarburization, (2) ferrite formation, (3) graphitization, (4) internal oxidation of the Si, (5) high temperature fatigue resistance, and (6) creep potential. Initial results obtained include microstructure examination after being exposed to high temperatures, grain size, nodule size, and hardness measurements. The initial examinations concluded that both cast irons performed fairly similarly, although the microstructure of the HSM samples did show slightly better resistance to high temperature as compared to that of the 50HS. Follow on work involved high temperature fatigue testing of these two materials in order to better determine if the newer alloy, HSM is a better choice for exhaust manifolds. Correlations between fatigue performance and microstructure were made and discussed, with the results examined in light of current and proposed models for predicting fatigue performance based on computational methods, to see if any suitable models exist that might be used to assist in designing with these cast alloys.