Diffusion tensor magnetic resonance imaging (DT-MRI) has been used to examine the microstructure of individual white matter tracts, often in neuropsychiatric conditions without identifiable focal pathology. However, the voxel-based group-mapping and region-of-interest (ROI) approaches used to analyse the data have inherent conceptual and practical difficulties. Taking the example of the genu of the corpus callosum in a sample of schizophrenic patients, we discuss the difficulties in attempting to replicate a voxel-based finding of reduced anisotropy using two ROI methods. Firstly we consider conventional ROIs; secondly, we present a novel tractography-based approach. The problems of both methods are explored, particularly of high variance and ROI definition. The potential benefits of the tractographic method for neuropsychiatric conditions with subtle and diffuse pathology are outlined.