While the disease has been studied for decades, the pathogenesis of pre-eclampsia remains mysterious. However, studies of the disease in humans are confounded by the fact that while the disease manifests in the second and third trimester its origins likely begin in the first trimester (Cross, 1996; Roberts and Cooper, 2001; Roberts and Lain, 2002). This makes defining both the etiology and the subsequent pathological events rather difficult, and researchers are limited to making inferences from pathological specimens, and distinguishing between primary and secondary events can be impossible. Despite these challenges, the fact that pre-eclampsia is strictly a disease of pregnancy indicates that the fetus and/or placenta interact with maternal factors to produce the disease. Indeed, several lines of evidence support the idea that placental development and/or function are abnormal in pre-eclampsia (Cross, 1996; Roberts and Cooper, 2001; Roberts and Lain, 2002). The strict requirement for a fetal–maternal interaction has led to the hypothesis that both feto-placental defects and maternal susceptibility to hypertensive and/or renal disease are required in order to initiate the disease (Cross, 1996; Lachmeijer et al., 2002; Roberts and Cooper, 2001; Roberts and Lain, 2002). However, as reviewed here, emerging evidence from mouse and rat models shows that pre-eclampsia can be initiated by multiple means, each producing all of the pathognomonic features of the disease – gestational hypertension, proteinuria and renal glomerular lesions (Davisson et al., 2002; Faas et al., 1995; Kanayama et al., 2002; Maynard et al., 2003; Sakawi et al., 2000; Wardle, 1976).