Understanding the mechanical properties of human teeth is important to clinical tooth preparation and to the development of "tooth-like" restorative materials. Previous studies have focused on the macroscopic fracture behavior of enamel and dentin. In the present study, we performed indentation studies to understand the microfracture and deformation and the microcrack-microstructure interactions of teeth. It was hypothesized that crack propagation would be influenced by enamel rods and the dentino-enamel junction (DEJ), and the mechanical properties would be influenced by enamel rod orientation and tooth-to-tooth variation. Twenty-eight human third molars were used for the measurement of hardness, fracture toughness, elastic modulus, and energy absorbed during indentation. We examined the effect of enamel rod orientation by propagating cracks in the occlusal surface, and in the axial section in directions parallel and perpendicular to the occlusal surface. The results showed that the cracks in the enamel axial section were significantly longer in the direction perpendicular to the occlusal surface than parallel. The cracks propagating toward the DEJ were always arrested and unable to penetrate dentin. The fracture toughness of enamel was not single-valued but varied by a factor of three as a function of enamel rod orientation. The elastic modulus of enamel showed a significant difference between the occlusal surface and the axial section. It is concluded that the cracks strongly interact with the DEJ and the enamel rods, and that the mechanical properties of teeth are functions of microstructural orientations; hence, single values of properties (e.g., a single toughness value or a single modulus value) should not be used without information on microstructural orientation.