Understanding the mechanisms of virus-host interactions is crucial for advancing our knowledge of viral pathogenesis and developing effective antiviral strategies. As novel, highly virulent pathogens continue to emerge, overcoming the challenges in virus-host biology and infection control is more important than ever. The CRISPR-Cas system has revolutionized genetic engineering, offering a precise and efficient application in synthetic biology. It is also invaluable in virology research, diagnostics, and antiviral therapeutics. In this review, we explore the latest advances in CRISPR-Cas-based approaches to elucidate virus-host interactions, focusing on the identification of key receptors and host factors essential for virus infection. Furthermore, we discuss the potential of the CRISPR-Cas system as an antiviral strategy for tackling newly emerging and re-emerging viruses. Finally, we discuss the potential of CRISPR-Cas-based gene editing for the development of innovative viral vaccines.