Hot flashes represent one of the most bothersome complaints in breast cancer survivors. In the last two decades, studies investigated several agents and natural compounds to treat these symptoms. Hormones such as estrogens and progestins remain the most beneficial treatment. However, many physicians and patients are reluctant to use these therapies because of the controversy regarding the hormonal effects on tumor growth and progression. Unfortunately, most natural and nonconventional remedies that have been scientifically investigated appear disappointing. Selective serotonin re-uptake inhibitors and other agents that seem to work in similar ways have been investigated over the last few years in Phase II and III trials. Mature results from two prospective, randomized, placebo-controlled trials reveal that selective serotonin re-uptake inhibitors are well tolerated, reduce hot flashes by 50%-60%, and improve sleep and libido. Selective serotonin re-uptake inhibitors should be considered as a first-line nonhormonal pharmacologic therapy for women with menopausal symptoms.