The use of estrogenic compounds as antidepressants or as coadjuvants to facilitate the effect of antidepressants has reported controversial results, suggesting that many factors could influence their actions. This review analyzes, from a basic research perspective, the possible factors that may underlie the antidepressant action of estrogens alone or in combination. The possible mechanisms of action of estrogens alone and in combination with the selective serotonin reuptake inhibitor, fluoxetine, the selective noradrenaline reuptake inhibitor, desipramine, and the mixed serotonin/noradrenaline reuptake inhibitor, venlafaxine are reviewed, focusing on monoaminergic systems and estrogen receptors as main targets. The antidepressant effect of estrogens depends on the type of estrogen, treatment duration, doses, sex, time after ovariectomy, and age. Estrogens potentiate the antidepressant-like action of fluoxetine, venlafaxine, and desipramine and drastically shorten their latency of action. The antidepressant-like effect of estrogens alone or in combination with antidepressants seems to be mediated by monoaminergic and classic estrogen receptors, as WAY100635, an antagonist to the serotonin 1A receptor, idaxozan, an antagonist to alpha2 adrenergic receptors, and RU 58668, an estrogen receptor antagonist, blocked their antidepressant-like effect. In conclusion, estrogens produce antidepressant-like actions by themselves and importantly facilitate the action of clinically used antidepressants.