During the past two decades, the emerging human coronavirus (HCoV) outbreaks have posed severe threats to global public health and economic development, as illustrated in the current COVID-19 pandemic, thus calling for the development of pan-CoV inhibitors. Based on our previous experience in the development of peptide-based viral fusion inhibitors against HIV (Nature 1993; 365: 113), SARS-CoV (Lancet 2004; 363: 938), MERS-CoV (Nat. Commun. 2014; 5: 3067), we designed and developed the first pan-CoV fusion inhibitor, EK1, which is effective against all human coroviruses (HCoVs) tested (Sci. Adv. 2019; 5: eaav4580). EK1 peptide is now under clinical trial for treatment of SARS-CoV-2-infected patients. We then further modified EK1 by conjugating cholesterol to its C-terminus. One of the lipopeptides, EK1C4, is about 240- and 150-fold more potent than EK1 against SARS-CoV-2 spike protein-mediated membrane fusion and pseudovirus infection, respectively. It is also very effective against infection by other HCoVs, including SARS-CoV and MERS-CoV, and SARS-related CoVs (Cell Res. 2020; 30: 1343-355). Notably, both EK1 and EK1C4 are potent in inhibiting infection by SARS-CoV variants, including Omicron (Cell Res. 2022; 32: 404-4065). Intranasal administration of EK1C4 to hACE-transgenic mice before or after challenge with SARS-CoV-2 protected mice from infection (Signal Transduct. Target Ther. 2021; 6: 288.). All these results suggest that EK1 and its lipopeptides can be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and its variants, as well as other emerging and reemerging HCoV diseases in the future.