Viruses, as obligatory parasites, depend on cellular factors and their associated processes to enter the host cells, replicate their genome, assemble progeny viruses, and disseminate. Identifying the host factors that provide assistance to clinically relevant viruses in each step of virus infection cycle could provide valuable new targets for antiviral therapy. In addition to treatment with canonical antivirals that directly target the viruses, a complementing strategy is to develop antiviral agents that interfere with host cell processes that are essential for the viruses for productive replication and spread. If the host cell processes shared by multiple viruses are charted and pharmacologically targeted without affecting critical cell functions, it should be possible to broadly inhibit the replication and transmission of emerging viruses. Moreover, identification and characterization of host molecules involved in virus infection processes can provide new insights into the mechanisms by which viruses invade the host cells and complete their life cycle. Recently, genome-wide CRISPR-Cas screens are being increasingly employed to identify host factors essential for viruses to establish infection and spread. CRISPR-Cas technology also offers to target candidate factors and illuminate virus-host interactions that have so far remained elusive. The relative ease of use and reproducibility of CRISPR-Cas has emerged as an exciting tool to identify previously unrecognized host proteins, improve our understanding of virus infection mechanisms, and illuminate potentially valuable antiviral targets for prophylactic and therapeutic interventions.