Gaining a mechanistic understanding of the mechanical properties of mineralized tissues, such as dentin and cortical bone, is important from the perspective of developing a framework for predicting and preventing failure of teeth and whole bones, particularly with regard to understanding the effects of microstructural modifications from factors such as aging, disease, or medical treatments. Accordingly, considerable research efforts have been made to determine the specific mechanisms involved in the fatigue and fracture of mineralized tissues, and to discover how these mechanisms relate to features within the respective microstructures. This article seeks to review the progress that has been made specifically in the area of fatigue, focusing on the research that moves our understanding beyond simple fatigue life (S/N) concepts and instead addresses the separate mechanisms for microdamage initiation, crack propagation, and in the case of bone, repair and remodeling.