Increasing bodyweight among women worldwide seems to be associated with a proportional rise in the number of women developing breast cancer. It is of utmost importance to obtain reliable biomarkers that may help clinicians to identify susceptible individuals among the growing population of women with excess adiposity. Our recent studies, reviewed within this article, support that adiposity-related metabolic disorders may represent high-risk phenotypes; specifically, we conclude that a low level of high-density lipoprotein cholesterol may be a reliable marker for breast cancer risk among overweight women. We tested our hypothesis among a large number of overweight women in the Norwegian Three County Cohort and the Norwegian cross-sectional study, the Energy Balance and Breast cancer Aspects (EBBA-I) study. Future studies should explore how genetic, environmental and behavioral factors may increase the susceptibility of overweight women to breast cancer, and how we can successfully establish targeted preventive strategies.