Understanding the role of extracellular RNA (exRNA) has emerged as an exciting avenue for biomarker, therapeutic, as well as basic cell-cell communication applications and discoveries. Multiple protocols, kits, and procedures have been developed in the last decade to allow fractionation as well as isolation of subpopulations of macromolecules of interest found in biofluids. Here, we introduce the protocols decision tree developed by the Extracellular RNA Communication Consortium and available on their website (exRNA portal), and compare all methods currently available to the exRNA field and report pros and cons for each platform.