The placenta is a transient organ that is critical for the growth and development of the mammalian embryo. Placental insufficiencies can lead to preeclampsia in the mother and intra-uterine growth restriction of the fetus. Insults incurred in utero have been associated with increased susceptibility to cardiovascular disease and diabetes in adulthood. A functional placenta develops through a delicate interplay of its vascular and trophoblast compartments. However, the genetic basis of trophoblast development and placental angiogenesis is not completely understood. In this thesis, using a mouse model, I have studied the role of a micro-RNA, miR-126, in placental development. Additionally, I also uncovered a novel role for miR-126 in regulating glucose homeostasis in adults. The first set of studies elucidates the role of miR-126 in the murine placenta. Here, I determined the role of miR-126 in placental development, using a mouse model with a targeted deletion of miR-126. miR-126 has a novel expression domain in trophoblast stem cells and differentiated trophoblast sub-types in the placenta. Loss of miR-126 leads to significant hyperplasia in the junctional zone at embryonic day 15.5 (E15.5) at the expense of the labyrinth, resulting in reduced placental volume for nutrient exchange and intra-uterine growth restriction of the embryos. Junctional zone hyperplasia results from increased numbers of proliferating glycogen trophoblast progenitors at E13.5 that give rise to an expanded glycogen trophoblast population at E15.5. I also demonstrate that miR-126-/- placentas display aberrant expression of imprinted genes with important roles in glycogen trophoblasts and junctional zone development, including Igf2, H19, and Cdkn1c. Abnormal imprinted gene expression is restricted to the placenta and is accompanied by aberrant DNA methylation at imprint control centers. miR-126-/- placentas also display abnormal expression of the imprinting regulator, Dnmt1, through early and mid-gestation and display changes in global methylation at mid-gestation. Collectively, using a miR-126 loss of function mouse model, I have identified a novel role for miR-126 in regulating DNA methylation, imprinted gene expression and glycogen trophoblast proliferation in the placenta. The second set of studies focused on the role of miR-126 in glucose metabolism. A number of rare autosomal dominant, monogenic forms of diabetes termed maturity onset diabetes (MODY) have been identified in humans. miR-126+/- adult mice display fasting hyperglycemia and hypoinsulinemia. miR-126+/- male mice, but not female mice display sporadic weight-gain defects and severe glucose intolerance during a glucose tolerance test. This indicates that loss of even a single copy of miR-126 is associated with metabolic dysfunction thereby highlighting its importance in maintaining glucose homeostasis. Collectively, my studies uncovered a novel role for miR-126 in regulating DNA methylation and extra-embryonic energy stores in the placenta. In addition, my studies uncovered a potential novel role for miR-126 in regulating glucose homeostasis in adult mice.