Technical Abstract: Honey bee colonies are vulnerable to parasites and pathogens ranging from viruses to vertebrates. An increasingly prevalent disease of managed honey bees is caused by the microsporidian, Nosema ceranae. Microsporidia are basal fungi and obligate parasites with much reduced genomic and cellular components. A recent genome sequencing effort for N. ceranae indicated the presence of machinery for RNA silencing in this species, suggesting that RNA interference (RNAi) might be exploited to regulate Nosema gene expression within bee hosts. Here we use controlled laboratory experiments to show that double-stranded RNA homologous to specific N. ceranae ADP/ATP transporter genes can specifically and differentially silence transcripts encoding these proteins. This inhibition also affects Nosema levels and host physiology. Gene silencing could be mediated solely by Nosema or in concert with known systemic RNAi mechanisms in their bee hosts. These results are novel for the microsporidia and provide a possible avenue for controlling a disease agent implicated in severe honey bee colony losses. Moreover, since microsporidia are pathogenic in several known veterinary and human diseases, this advance may have broader applications in the future for disease control.