Chronic stressful life events are risk factors for developing major depression, the pathophysiology of which is strongly linked to impairments in serotonin (5-HT) neurotransmission. Exposure to chronic unpredictable stress (CUS) has been found to induce depressive-like behaviours, including passive behavioural coping and anhedonia in animal models, along with many other affective, cognitive, and behavioural symptoms. The heterogeneity of these symptoms represents the plurality of corticolimbic structures involved in mood regulation that are adversely affected in the disorder. Chronic stress has also been shown to negatively regulate adult hippocampal neurogenesis, a phenomenon that is involved in antidepressant effects and regulates subsequent stress responses. Although there exists an enormous body of data on stress-induced alterations of 5-HT activity, there has not been extensive exploration of 5-HT adaptations occurring presynaptically or at the level of the raphe nuclei after exposure to CUS. Similarly, although hippocampal neurogenesis is known to be negatively regulated by stress and positively regulated by antidepressant treatment, the role of neurogenesis in mediating affective behaviour in the context of stress remains an active area of investigation. The goal of this review is to link the serotonergic and neurogenic hypotheses of depression and antidepressant effects in the context of stress. Specifically, chronic stress significantly attenuates 5-HT neurotransmission and 5-HT1A autoreceptor sensitivity, and this effect could represent an endophenotypic hallmark for mood disorders. In addition, by decreasing neurogenesis, CUS decreases hippocampal inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, exacerbating stress axis overactivity. Similarly, we discuss the possibility that adult hippocampal neurogenesis mediates antidepressant effects via the ventral (in rodents; anterior in humans) hippocampus' influence on the HPA axis, and mechanisms by which antidepressants may reverse chronic stress-induced 5-HT and neurogenic changes. Although data are as yet equivocal, antidepressant modulation of 5-HT neurotransmission may well serve as one of the factors that could drive neurogenesis-dependent antidepressant effects through these stress regulation-related mechanisms.