In pregnancy, the maternal immune system is regulated to tolerate the developing semi-allogeneic fetus. Systemic immunological changes can be detected which were historically described as being biased away from a graft rejecting ‘type 1’ pro-inflammatory phenotype, and towards a more tolerising B cell/antibody driven ‘type 2’ anti-inflammatory cytokine immunity. This hypothesis is now considered to be too simplistic and has been adapted in the light of more recent research. It is now apparent that normal pregnant women actually show mild systemic inflammation, when compared to non-pregnant women, although there is still a skewing of immune responses towards ‘type 2’. In this chapter we discuss the clinical and experimental evidence for these changes, which may be induced by a multitude of factors secreted from the placenta into the maternal blood These factors include cytokines, hormones, HLA-G, danger molecules and extra cellular vesicles from the syncytiotrophoblast layer. They interact with both the immune and endothelial systems and contribute to a healthy pregnancy. Deregulation of these factors may lead to the development of pre-eclampsia, in which there is excessive maternal systemic inflammation along with endothelial dysfunction, endangering the lives of both mother and baby.