Exosome extracellular vesicles as biologic therapy for COVID-19 therapy are discussed for two areas. The first involves growing use of mesenchymal stromal cells (MSC) for the profound clinical cytokine storm and severe pneumonia in Covid-19 patients. Instead, it is recommended to switch to treat instead with their MSC-released exosomes. This is because many reports in the literature of have shown definitively that the release of exosomes from the in vivo administered MSC is actually responsible for their beneficial effects. Further, the exosomes are superior, simpler and clinically more convenient compared to their parental MSC. Additionally, in the context of COVID-19, the known tendency of MSC to aggregate causing lung dysfunction might synergize with the pneumonia aspects, and the tendency of MSC peripheral vascular micro aggregates might synergize with the vascular clots of the COVID-19 disease process, causing significant central or peripheral vascular insufficiency. The second involves use of COVID-19 convalescent plasma for its content of acquired immune antibodies that must consider the role in this therapy of billions of exosomes in the plasma. Many of these derive from activated immune modulating cells and likely transfer miRNAs that acting epigenetically to also influence the recipient response to the virus. These immune activated plasma exosomes may either be responsible for positive effects of the plasma beyond the contained immune antibodies, or could be inhibitory. Pre selection of plasma with the best antibodies and the best exosomes would produce the most optimum therapy for very severely affected COVID-19 patients.