In this study, we minimize uncertainty in Diffusion Tensor Imaging (DTI) parameters by optimally selecting diffusion gradient directions utilizing prior structural knowledge. By measuring the anatomy of the spinal cord for each subject, we created patient-specific, anatomically-informed DTI encoding schemes for 256 subjects, utilizing just 6 diffusion directions. In addition, we create an optimal encoding 6-direction scheme for the anatomically-average person. Through simulations and experimental validation on a physical fiber phantom, we show improvements in FA estimation, even when compared to conventional 30 direction schemes. This technique results in minimal scan time and increased accuracy in order to maximize clinical value.