Endometrial cancer (EC) is the commonest gynaecological cancer in North American and European women. Even though it has been shown that women with polycystic ovary syndrome (PCOS) have a three-fold increase in the risk of developing EC compared to women without PCOS, the precise molecular mechanisms which increase EC risk in women with PCOS remain unclear. Clinical strategies to prevent EC in PCOS are therefore not well researched and understood. Although raised estrogen levels, hyperinsulinaemia and, reduced apoptosis have been suggested as potential mechanisms, there is a lack of clarity about how these factors and other factors may interact to increase EC risk in PCOS. This article reviews the literature, on the potential molecular links between PCOS and EC but argues for a paradigm shift, to a systems biology-based approach in future research into the molecular links between PCOS and EC. The potential challenges of a systems biology-based approach are outlined but not considered insurmountable.