Hormone replacement therapy (HRT) is recognized as the 'gold standard' for the treatment of the short- and long-term consequences of estrogen deprivation. Compliance with HRT is poor, mainly due to side-effects and fear of cancer. Many women discontinue the treatment prematurely and will not derive its full benefit. This presentation summarizes the results of studies assessing the safety and tolerability of pulsed estrogen therapy (Aerodiol) versus conventional estrogen therapy. The mammary safety was assessed in well-recognized experimental models. In comparison with oral administration, pulsed therapy showed a significantly lower rate of tumor induction (p < 0.05) and reduced tumor growth. The endometrial safety of Aerodiol was assessed in a long-term study. After 1 year of treatment, 311 biopsies could be evaluated: 34% were atrophic, 16% proliferative, 39% secretory, 4% menstrual and 7% had no endometrial tissue. No cases of endometrial hyperplasia or cancer were detected. In a comparative study comprising 659 women, a lower frequency of irregular bleeding was reported with Aerodiol compared with orally administered estradiol. In two randomized studies, the frequency of mastalgia has been found to be significantly lower with Aerodiol compared with orally and transdermally administered estradiol. Aerodiol has been found to be well-tolerated, with better gynecological acceptability than conventional estrogen, and individualization of therapy might increase compliance. Intranasally administered estradiol is an attractive alternative for many women.