Hot flashes are very common in women in menopause and can have a detrimental effect on quality of life. Hormone therapy (estrogen with or without progestin) remains the gold standard treatment for hot flashes, but concerns for the risk of hormone therapy have resulted in its decline and a demand for nonhormonal treatments with demonstrated efficacy for hot flashes. Several nonhormonal therapies have been tested in randomized placebo-controlled trials including nonpharmacologic approaches and pharmacologic nonhormonal agents. Among them, two classes of nonhormonal medications have been demonstrated to effectively alleviate hot flashes: γ-aminobutyric acid (GABA) analogs and selective serotonin reuptake inhibitors (SSRIs). This article discusses the superior efficacy of the newer nonhormonal prescriptions for the treatment of hot flashes when compared with estrogen replacement therapy, and provides some recommendations regarding use of them in peri- and postmenopausal women.