This review summarizes epidemiological data linking the fatty acid desaturation index measured in blood lipids, as a biomarker of hepatic stearoyl-CoA desaturase activity, the key enzyme involved in the synthesis of monounsaturated fatty acids from saturated fatty acids, to breast cancer risk. The biological plausibility of this association is discussed. Epidemiological cohort studies reported an association between a high saturated to monounsaturated fatty acid ratio measured in blood lipids, indicating low stearoyl-CoA desaturase-1 activity, and decreased breast cancer risk. The suppression of stearoyl-CoA desaturase expression reduces cancer cell proliferation and in-vitro invasiveness, and dramatically impairs tumor formation and growth. These effects could not be overcome by supplying exogenous monounsaturated fatty acids. Epidemiological findings, in accordance with experimental data, suggested that decreased hepatic stearoyl-CoA desaturase expression/activity may be related to decreased risk of breast cancer.