Pregnancy is a unique and well-choreographed physiological phenomenon that involves dynamic maternal and fetal dialogue. Local immune tolerance, angiogenesis, cytokine and hormonal balance, cellular and molecular mimicry, genetic and epigenetic as well as environmental cues influence the pregnancy outcomes. Adverse pregnancy outcomes are a consequence of impairment of more than one of these factors that results in adaptation failure. In this chapter, we propose a two hit hypothesis for adverse pregnancy outcomes (Fig. 1) with particular focus on gene-environment interactions, as we understand them through the prism of interleukin (IL-10) and a decade of research with IL-10-/- mice.