Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significant morbidity and mortality. Despite advances in the treatment of major depression, one-third of depressed patients fail to respond to conventional antidepressant medication. One pathophysiologic mechanism hypothesized to contribute to treatment resistance in depression is inflammation. Inflammation has been linked to depression by a number of putative mechanisms involving perfusion deficits that can trigger microglial activation and subsequent neuroinflammation in the elderly. However, the pathophysiological mechanisms remain to be further elucidated. This review focusses on recent studies addressing the complex relationships between depression, aging, inflammation and perfusion deficits in the elderly. We expect that a better understanding of neuroinflammatory mechanisms associated with age-related diseases may lead to the discovery of new biomarkers of MDD and development of new therapeutic interventions.