Post-stroke depression (PSD) has become a prominent negative factor of stroke recovery. Different etiological mechanisms may be involved, and there forms two major hypotheses: biological hypothesis and psychological hypothesis. Biological hypothesis included four mechanisms: lesion location mechanism, neurotransmitters mechanism, inflammatory cytokines mechanism and gene polymorphism mechanism. As for lesion location, the specific location of a lesion (e.g., basal ganglia or left frontal lobe lesions) played an important role in the etiology of PSD. For neurotransmitters, decreased serotonin and norepinephrine in the brain were associated with PSD. In inflammatory cytokines, increased cytokines [including interleukin (IL) 1beta, IL-18, tumor necrosis factor alpha] after stroke lead to depression. For gene polymorphism, there was significant association between serotonin transporter gene-linked promoter region short variant genotype and post-stroke major depression. Psychological hypothesis suggested that social and psychological stressors associated with stroke may be the primary cause of depression. Up to now, there is no definitive evidence to support or refute either a solely biological or solely psychosocial mechanism. It appears to be a kind of biopsychosocial multifactorial mental illness.