Compared with other vaccine types such as inactivated virus and viral-vectored vaccines, SARS and MERS subunit vaccines are much safer and do not cause obvious side effects. However, these subunit vaccines may face some important challenges, mostly arising from their relatively low immunogenicity, which must be combined with appropriate adjuvants or optimized for suitable protein sequences, fragment lengths, and immunization schedules. In addition, structure and epitope-based vaccine design has become a promising strategy to improve the efficacy of subunit vaccines. This is evidenced by a structurally designed MERS-CoV RBD-based protein which has significantly improved neutralizing activity and protection against MERS-CoV infection (Du et al., 2016a). It is prospected that more structure-guided novel strategies will be developed to improve the overall immunogenicity and efficacy of subunit vaccines against emerging pathogenic human coronaviruses, including those targeting SARS-CoV and MERS-CoV. Although a large number of SARS and MERS subunit vaccines have been developed with potent immunogenicity and/or protection in available animal models, virtually all remain in the preclinical stage. It is thus expected that one or several of these promising subunit vaccines can be further processed into clinical trials to confirm their immunogenicity against viral infections in humans.