Self-replicating proteins or prions deviate from the central dogma of replication. The discovery of prion-like domains in coronavirus SARS-CoV-2 suggests their possible role in viral evolution. Here, we have outlined the possible role of self-replicating protein-like domains in the emergence of novel viruses. Further studies are needed to understand the function of these viral self-replicating protein-like domains and whether they could be antiviral target(s) for the development of effective antiviral agents in the future.