The placenta is vital to fetal growth and development, as it bridges the fetus and the mother. Genome-wide epigenetic regulations (e.g., DNA methylation, histone modifications, non-coding RNAs) participate in many aspects of placenta development, including decidua of the uterus, trophoblast cell adhesion and invasion, angiogenesis and placental imprinted gene expression. Environmental factors during pregnancy, such as heavy metals, chemical compounds, modern assisted reproductive technology and the nutrient conditions, may cause abnormal placental epigenetics. Furthermore, sex differential expression of placental genes also contributes to epigenetic modifications. As prenatal DNA methylation analysis can detect abnormal epigenetic modifications, it is a potential diagnosis tool for early stage diseases and may help disease intervention and treatment. Here, we review not only regulations of epigenetic modifications during development of the placenta, but also the influences of environmental factors. The potential value for diagnosis and treatment is also discussed.