The coronavirus disease 2019 (COVID-19) is caused by a novel RNA enveloped coronavirus, SARS-CoV-2 when the virus enters human airway cells via an ACE2-mediated entry process. This entry pathway is facilitated by the cell surface heparan sulfate proteoglycan (HSPG), which enhances viral attachment to the cell surface. Researchers at NIDDK and NCATS have discovered a collection of FDA-approved drugs that can interfere with the entry of SARS-CoV-2. These drugs can be grouped into three classes based on the distinct steps in the viral entry pathway that they target. Specifically, Mitoxantrone, Raloxifene, and Piceatannol bind to heparan sulfate; Sunitinib and BNTX target the actin cytoskeleton and Tilorone inhibits lysosomes. Strikingly, drugs targeting distinct entry steps can be combined in vitro to achieve a synergized anti-SARS-CoV-2 activity either against Spike-bearing pseudoviral particles or authentic SARS-CoV-2. Given that the safety of these drugs have been well documented in previous clinical studies, it is well positioned to advance these drugs to clinical studies to test their efficacy as a COVID-19 therapy.