Given the importance of GRP78 in various biological processes, the interaction with SARS-CoV-2 protein, and the association with COVID-19 pathological risks, targeting either the activity or the expression of GRP78 could be an efficient therapeutic/preventative strategy to dampen the multiple stages of the SARS-CoV-2 life cycle including the binding, entry, replication, egress, and stability. The gene discussed is HSPA5; the disease is COVID-19.