The global pandemic of COVID-19 respiratory infection has prompted urgent need for novel therapies. Clinical and basic science investigators need to take the lead by promoting and adhering to rigorously designed investigations logically based on available pre-clinical data. The limited available data regarding MSC administration in pre-clinical respiratory disease injury models and current understanding of potential mechanisms of MSC actions in lung injury models can be cautiously and carefully utilised to support rationally designed and conducted clinical investigations. However, more pre-clinical data are necessary, particularly in models of coronavirus-induced lung injuries. While compassionate use of unproven MSC-based therapies may be contemplated in different circumstances, we urge that, whenever possible, this takes place in the larger context of a clinical investigation. Since the original writing of this review, a number of academic and industry-sponsored trials of MSC-based investigations have been initiated globally in addition to the ones in China reviewed here. We urge all of these to uphold the highest standards for rational and appropriately designed investigations. Only in these ways can a rational evidence-based platform for potential therapeutic use of cell-based therapies be developed.