A mechanistic understanding of fracture in human bone is critical to predicting fracture risk associated with age and disease. Despite extensive work, a mechanistic framework for describing how the microstructure affects the failure of bone is lacking. Although micromechanical models incorporating local failure criteria have been developed for metallic and ceramic materials, few such models exist for biological materials. In fact, there is no proof to support the widely held belief that fracture in bone is locally strain-controlled, as for example has been shown for ductile fracture in metallic materials. In the present study, we provide such evidence through a novel series of experiments involving a double-notch-bend geometry, designed to shed light on the nature of the critical failure events in bone. We examine how the propagating crack interacts with the bone microstructure to provide some mechanistic understanding of fracture and to define how properties vary with orientation. It was found that fracture in human cortical bone is consistent with strain-controlled failure, and the influence of microstructure can be described in terms of several toughening mechanisms. We provide estimates of the relative importance of these mechanisms, such as uncracked-ligament bridging.