HtrA3 is a serine protease of the mammalian HtrA (high temperature requirement factor A) family, which are known to play important roles in protecting cells from stress conditions such as heat shock, oxidative stress, inflammation, ischemia and cancer. We cloned HtrA3 and demonstrated its strong expression during placental development in the mouse, rhesus monkey and human. In mice, HtrA3 is primarily produced in the maternal decidua anchoring the placenta, and in the placental cells responsible for the nutrient and oxygen exchange. We also reported the association in women between HtrA3 dys-regulation during placental development and the subsequent development of pregnancy diseases such as preeclampsia, and the down-regulation of HtrA3 in a number of cancers such as endometrial and ovarian cancers. In this study, we knocked out (KO) HtrA3 from the mouse genome and established an HtrA3-KO mouse model. HtrA3-KO mothers could reproduce but gave birth to intra-uterine growth restricted (IUGR) offspring due to placental insufficiency. Detailed analysis of the HtrA3-KO placentas revealed a clear disorganization of the vasculature in the labyrinth, providing strong evidence that HtrA3 is critical for placental development and function. Furthermore, examination of the growth characteristics of the IUGR offspring revealed the following: catch-up growth occurred as early as 6 weeks after birth, by 34 week of age those were smaller in utero gained significantly higher body weight, this difference was strongly associated with their intra-uterine environment (the genotype of the mother) irrespective of their own genotype, and the major contributor to the heavier body weight was the larger mass of white adipose tissue. This study thus demonstrated the importance of HtrA3 in placental development and the long-term health consequences of placental insufficiency.