Introduction: Although postnatal depression is now well recognized, there is also a risk of depressive symptoms during perimenopause. The mechanisms underlying perimenopausal depression are still poorly understood; however, there are available treatment options. Areas covered: This review describes: the current pharmacotherapeutic approaches for perimenopausal depression, their strengths and weakness, and provides recommendations on how current treatment can be improved in the future. An electronic search identified specific guidelines for the treatment of perimenopausal depression released in 2018, as well as recent clinical studies on the subject. Expert opinion: The 2018 guidelines recommend selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) as front-line medications for perimenopausal depression, but SSRIs and SNRIs are not always effective. The efficacy of estrogen in perimenopausal depression is well documented, but estrogen is not FDA-approved to treat mood disturbances in perimenopausal women. Clinical practice guidelines currently recommend to restrict hormone therapy to the symptomatic treatment of menopause (not for the prevention of chronic diseases). Research with new estrogenic compounds is under way to improve their benefit/risk ratio in perimenopausal depression.