The menopause-related decline in estrogen levels leads to an array of genital, sexual, and urinary symptoms collectively known as genitourinary syndrome of menopause. The constellation of symptoms associated with vulvar and vaginal atrophy (VVA) can have a profoundly detrimental effect on a woman’s sexual function, relationships, and quality of life. Ospemifene is a selective estrogen receptor modulator indicated for treatment of moderate-to-severe symptomatic VVA in postmenopausal women who are not candidates for local vaginal estrogen therapy or have contraindications for estrogen products. Ospemifene is administered orally, thus avoiding the inconveniences of local therapy, and can be used in women with VVA and a history of breast cancer after completing all (including adjuvant) breast cancer treatment. As well as restoring vaginal health in symptomatic VVA, ospemifene may have collateral benefits of importance to postmenopausal women. In this Special Issue entitled “Treatment of Vulvar and Vaginal Atrophy: Clinical Experience with Ospemifene,” illustrative case studies examine the experiences of women with VVA during treatment with ospemifene. Specific topics include the effects of ospemifene on bone markers; its use in breast cancer survivors and in women with dyslipidemia, urinary incontinence, or VVA-related sexual dysfunction; and its concomitant use with laser therapy.