MicroRNAs play a variety of roles during development, primarily by regulating gene expression through repression of target mRNAs. One cluster, the miR-290 cluster, is specific to placental mammals, and has, in the past, been linked to pluripotency maintenance in the early mammalian embryo. On p. 3731, Robert Blelloch and colleagues now uncover a role for the miR-290 cluster in placental development. Using transgenic mouse lines, they find that the miR-290 cluster is highly expressed during early mouse embryogenesis and becomes restricted to the trophoblast from gastrulation up until birth. When the miR-290 cluster is deleted, mRNAs targeted by this cluster become dysregulated. Interestingly, this deletion also causes several placental defects, including a reduction in trophoblast proliferation, reduced giant cell endoreduplication, and disruption of the vasculature of the placental labyrinth. Ultimately, this results in the development of a placenta that is reduced in size, and defective in passive diffusion of nutrients from the mother to the foetus, leading to late embryonic lethality. These results suggest that microRNAs within the miR-290 cluster are responsible for regulating the gene network important for placental growth and development in mice, and may provide insight into the evolution of eutherian mammals.