Disruption of placental gene expression contributes to several congenital developmental disorders in humans, and may play an important role in the evolution of reproductive barriers between species. The placenta is also highly enriched for interacting genes showing parent-of-origin or imprinted expression, which is thought to have evolved to mitigate parental conflict within this extra-embryonic tissue. However, relatively little is known about the broader organization, functional integration, and evolution of placental gene expression networks across species. Here we used a systems genetics approach to examine the genetic and regulatory underpinnings of placental overgrowth in hybrids between two species of dwarf hamsters (Phodopus sungorus and P. campbelli). Using quantitative genetic mapping and mitochondrial substitution lines, we show that the X chromosome is the major maternal factor explaining massive parent-of-origin dependent placental overgrowth in hybrids. Mitochondrial interactions did not contribute to abnormal hybrid placental development, and there was only weak correspondence between placental disruption and early embryonic growth phenotypes. In parallel, genome-wide analyses of placental transcriptomes from the parental species and first and second-generation hybrids revealed a central group of co-expressed X-linked and autosomal genes that were highly enriched for maternally-biased expression. Expression of this core placental regulatory network was strongly correlated with placental growth and showed widespread misexpression dependent on epistatic interactions with X-linked hybrid incompatibilities. Silencing of the paternal X chromosome and most candidate paternally imprinted autosomal genes appeared unperturbed in the same genetic crosses. Collectively, our results indicate that the X chromosome plays a prominent role in the evolution of placental gene expression and the rapid accumulation of hybrid developmental barriers between mammalian species.