Reverse vaccinology uses computational approaches to identify potential vaccine candidates. With the increasing pace of genome sequencing, it is possible to identify all potential antigens from any sequenced pathogen. Reverse vaccinology uses computational data to identify potential antigens, express those potential antigens, and then screen them further for protective immune response. Thus, reverse vaccinology offers several advantages and enables identifying novel antigens even if the expression level is low or not abundant. Besides, reverse vaccinology approaches offer reduced time and reduced cost for the development of vaccines compared to conventional vaccination methods. Such a timely, speedy, and economical process for developing vaccines without compromising safety and immunogenicity is the urgent need of the hour to combat many emerging pathogens, including SARS-CoV-2. This chapter summarizes approaches and challenges in developing vaccines against many emerging pathogens, including SARS-CoV-2, by employing this innovative strategy.