Both insulin resistance and estrogen deficiency result in complex metabolic disorder based mainly on defective cellular glucose uptake and on an atherogenic serum lipid profile. These alterations may be regarded as high risks for several life-threatening human diseases, such as type-2 diabetes, cardiovascular lesions and malignancies. Insulin resistance and estrogen deficiency are concomitant disorders with mutual interrelationship. Insulin resistance and the compensatory hyperinsulinemia provoke increased androgen synthesis at the expense of decreased estrogen production. Similarly, a moderate or severe decrease in serum estrogen levels enhances the prevalence of insulin resistant states both in men and women. Healthy premenopausal women enjoy the defensive effect of estrogens against metabolic and hormonal disorders. However, even a slight decrease in their circulatory estrogen levels associated with insulin resistance may increase the risk for cancers, particularly in the organs having high estrogen demand (breast, endometrium and ovary). On the other hand, postmenopausal state with profound estrogen deficiency confers high risk for cancers in different organs with either high or moderate estrogen demand. After menopause, hormone replacement therapy improves insulin sensitivity and decreases the enhanced inclination to malignancies in postmenopausal women. Recognition of the thorough interplay between insulin resistance and estrogen deficiency may illuminate many apparently controversial experimental and clinical findings concerning cancer development and therapeutic possibilities. Moreover, their interactions in the initiation and progression of human malignancies may supply new strategies in primary cancer prevention and cancer cure.