During daily activities, bone is exposed to repetitive loading, and over time, this can lead to failure. Cancellous bone is the primary load-bearing structure of human vertebral bodies, yet most studies of cancellous bone mechanical performance concentrate on uniaxial properties such as Young's modulus and strength. Mechanical properties of cancellous bone are caused by the accumulation of microdamage, local stress and strain, tissue material properties, and local geometry. In this thesis, I examine the mechanisms associated with fatigue failure of cancellous bone. I then apply the findings to the design of novel microarchitectured materials. To examine the mechanical performance of cancellous bone under fatigue, we submitted human vertebral cancellous bone to cyclic compressive loading to induce microdamage. We found that fatigue failure is caused primarily by the initial sites of microdamage accumulation. In cancellous bone, microdamage formed preferentially in the interior regions of trabeculae, distant from trabecular surfaces. The location of microdamage coincided with locations of greater concentrations of Advanced Glycation Products (AGEs), suggesting the interior regions of trabeculae are more brittle and susceptible to microdamage accumulation. Because local geometry influences failure of cancellous bone, we examined the microarchitectual features of cancellous bone that are associated with damage accumulation. We found that microdamage accumulation in cancellous bone was reduced in specimens with thicker transverse rod-like trabeculae. Early in fatigue life, disproportionately more rod-like trabeculae failed, suggesting the importance of transverse rod-like trabeculae in resisting fatigue failure. To further test the idea that rod-like trabeculae influenced fatigue failure, models of cancellous bone were generated using three-dimensional printing in which transverse rod thickness was increased in a controlled manner. The specimens were submitted to cyclic compressive loading. Increasing the thickness of transverse rod-like trabeculae substantially extended fatigue life. Next, we designed a repeating cellular solid that also demonstrates enhanced fatigue life due to alterations in transverse struts. In summary, both tissue material properties and microarchitecture of cancellous bone influence fatigue failure. Our findings suggest a previously unidentified design strategy of open cell foams in which the strut thickness transverse to loads determines fatigue life. The resulting low-density cellular structure has potential application in a variety of lightweight structures.