Pre-eclampsia, a life-threatening disease during pregnancy, is a leading cause of global maternal mortality. Although there is substantial evidence of a genetic background, the complexity of the processes involved and nature of the maternal-fetal phenomenon do not make the search for the causative genes easy. Recent retrospective studies on the subject suggest the heritable allelic variations, particularly the utero-placental renin-angiotensin system with defective placental vascular development, could become the cornerstone for the genetics of pre-eclampsia and hence might well be associated with such defective development. Moreover, the role of immune mechanisms (immune maladaptation) deserves not to be ignored. Large-scale studies entailing genomewide scanning, sib-pair linkage analysis, and family-based association studies with appropriate power to detect genes with a lower relative risk are necessary to understand the puzzle of the disease. Moreover, recently, the importance of epigenetic features and the effect of imprinted genes related to trophoblast growth as well as fetal development on hypertension in pregnancy have been highlighted. All these possibilities are intuitively attractive and are supported by some circumstantial evidence. Although the consistent tenor of a series of papers instill some confidence, we need meticulously designed larger-scale investigations including large numbers of affected women and their babies to provide the analytic stringency essential to study the polygenic multifactorial basis of pre-eclampsia.