A study published in *Nature* (477(7364): 340–343. doi:10.1038/nature10348) reveals that the cholesterol transporter Niemann-Pick C1 (NPC1) is essential for entry of Ebola (EboV) and Marburg (MarV) viruses into host cells. The research used a genome-wide haploid genetic screen in human cells to identify host factors required for EboV entry. The screen identified mutations in all six subunits of the HOPS multisubunit tethering complex and 39 mutations in NPC1, a protein involved in endo/lysosomal cholesterol transport. Cells deficient in HOPS or NPC1 were resistant to EboV and MarV infection but susceptible to other viruses. The study shows that NPC1 is required for membrane fusion mediated by filovirus glycoproteins and for viral escape from the vesicular compartment, independent of its role in cholesterol transport. The findings suggest that filoviruses use a unique entry pathway and highlight NPC1 as a potential target for antiviral therapies. The study also demonstrates that NPC1 is critical for authentic filovirus infection in human cells and in mouse models. The research underscores the importance of NPC1 in viral entry and pathogenesis, offering new insights into the mechanisms of filovirus infection and potential therapeutic strategies.A study published in *Nature* (477(7364): 340–343. doi:10.1038/nature10348) reveals that the cholesterol transporter Niemann-Pick C1 (NPC1) is essential for entry of Ebola (EboV) and Marburg (MarV) viruses into host cells. The research used a genome-wide haploid genetic screen in human cells to identify host factors required for EboV entry. The screen identified mutations in all six subunits of the HOPS multisubunit tethering complex and 39 mutations in NPC1, a protein involved in endo/lysosomal cholesterol transport. Cells deficient in HOPS or NPC1 were resistant to EboV and MarV infection but susceptible to other viruses. The study shows that NPC1 is required for membrane fusion mediated by filovirus glycoproteins and for viral escape from the vesicular compartment, independent of its role in cholesterol transport. The findings suggest that filoviruses use a unique entry pathway and highlight NPC1 as a potential target for antiviral therapies. The study also demonstrates that NPC1 is critical for authentic filovirus infection in human cells and in mouse models. The research underscores the importance of NPC1 in viral entry and pathogenesis, offering new insights into the mechanisms of filovirus infection and potential therapeutic strategies.