Background: Patients with treatment-resistant depression (TRD) commonly report significant disability together with an increased risk of functional impairment. Neuroimaging techniques have been used to investigate the neuropathology of this complex illness, but it is still quite unknown whether abnormalities in the integrity of white matter (WM) of specific brain areas may be considered as trait markers of TRD. Methods: Electronic databases were searched from 1980 to 2013. Nine studies-comprising a total of 228 subjects and 171 controls-fulfilled our inclusion criteria and were analyzed in the present overview. Results: Several cross-sectional studies showed the association between WM abnormalities and TRD. According to the selected studies, sub-callosal cingulated cortex (SCC) WM abnormalities were largely implicated in the pathogenesis of both major depressive disorder and TRD. However, alterations in cortical-limbic or cortical-subcortical circuits, particularly the left middle frontal gyrus (which is thought to have a major role in emotional regulation) may also be involved in the pathophysiology of TRD. Conclusion: TRD may be related to the presence of specific microstructural WM abnormalities. WM abnormalities of specific brain regions such as SCC may have a major involvement in the pathogenesis of TRD.