Automotive industry faces numerous evolutions regarding environment regulations and parts reliability. Through the specific case of a cylinder head, actual and forthcoming challenges for low-cycle and thermal–mechanical fatigue design in an industrial context are presented. With a description of current design approaches and highlighting limitations, this work focuses on variable loadings, constitutive models and their interaction with the environment, fatigue criteria, and structure validations, the four major steps to meet a reliable design. The need to carry out extended experimental databases for different complexity levels is emphasized to provide a better understanding of loadings and their impact on the strength of materials and structures, as well as the production of more physically-based models that are easier to identify and lead to higher levels of reliability in the thermal–mechanical design process.