BACKGROUND: The association between stroke and depression is well established and has been suggested to be bidirectional. Systemic immune activation, hypothalamic-pituitary-adrenal axis hyperactivity, physiologic changes in the perfusion of blood vessels, the downregulation of neurotrophic factors, and apoptosis and necrosis of neuronal, glial, and endothelial cells have been frequently implicated in this relationship. A better understanding of the biology of poststroke depression could be important for enhancing clinical management. We review the currently available biologic markers of stroke-associated depressive illness (i.e., neurophysiologic, neuroendocrine, immunologic, and neuroimaging markers as well as neurotrophic factors). METHODS: Search strategies included the electronic databases PubMed, PsycINFO, EMBASE, CINAHL, the Cochrane Library, and Proquest Dissertations (all records through June 2012), the reference lists of retrieved articles, the reference list of relevant reviews, and direct contact with authors of retrieved articles for any additional unpublished data. RESULTS: Thirty-three papers fulfilled the criteria for inclusion. We detected moderate effects for high postdexamethasone cortisol levels (odds ratio [OR] 3.28; 95% confidence interval [CI] 1.28-8.39; P = .01), lower serum brain-derived neurotrophic factor levels (standardised mean difference [SMD] -0.52; 95% CI -0.84 to -0.21; P = .001), smaller amygdala volumes (SMD -0.45; 95% CI -0.89 to -0.02; P = .04), and a small effect for overall brain perfusion reduction (SMD -0.35; 95% CI -0.64 to -0.06; P = .02), respectively, to poststroke depression. CONCLUSIONS: Cortisol-lowering therapies and those that increase blood flow and neurotrophic factors represent promising novel therapeutics for depression subtypes and may reduce the risk of depression in stroke patients.