There is an urgent need for antivirals to treat the newly emerged SARS-CoV-2 . To identify new candidates we screened a repurposing library of ∼3,000 drugs . Screening in Vero cells finds few antivirals, while screening in human Huh7.5 cells validate 23 diverse antiviral drugs . Extending our studies to lung epithelial cells, we find that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells . Entry in lung epithelial Calu-3 cells is pH-independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases . Moreover, we find 9 drugs are antiviral in respiratory cells , 7 of which have been used in humans, and 3 are FDA approved including Cyclosporine . We find that the antiviral activity of Cyclosporine is targeting Cyclophilin rather than Calcineurin revealing essential host targets that have the potential for rapid clinical implementation.