Here, we investigate the ultrastructural origins of the strength of bone, which is critical for proper physiological function. A combination of dual nanoindentation, three-dimensional elastic-plastic finite element analysis using a Mohr-Coulomb cohesive-frictional strength criterion, and angle of repose measurements was employed. Our results suggest that nanogranular friction between mineral particles is responsible for increased yield resistance in compression relative to tension and that cohesion originates from within the organic matrix itself, rather than organic−mineral bonding.