Small RNAs have been discovered in a wide variety of extracellular environments and are now thought to participate in communication between cells and even between different organisms and species. Helminths are parasitic worms that generally reside in extracellular niches in their hosts and can establish chronic infection through the release of immunomodulatory factors. Recent work has demonstrated that Extracellular RNA (exRNA) may be another class of immunomodulator secreted by helminths. Here we will detail what is known about small RNA pathways in helminth pathogens (focusing on nematodes) and mammalian hosts. We will then explore the computational challenges with identifying RNA-RNA interactions between 2 different species and the paradigm of RNA-RNA co-evolution that accompanies this. Finally we explore the lingering questions that require further investigation to understand the properties of exRNA that would enable it to function as an immunomodulator.