Immunocompromised individuals are at high risk of poor coronavirus disease 2019 (COVID-19) outcomes and demonstrate a lower immune response to COVID-19 vaccines, including to the novel mRNA vaccines that have been shown to elicit high neutralizing antibody levels. This review synthesized available data on the immune response to COVID-19 and critically assessed mRNA COVID-19 vaccine immunogenicity in this vulnerable subpopulation. Patients with various immunocompromising conditions exhibit diverse responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 severity and mortality, and available vaccines elicit lower immune responses, particularly in solid organ transplant recipients. Strategies to improve vaccine responses in immunocompromised individuals are being implemented in vaccine recommendations, including the use of a third and fourth vaccine dose beyond the two-dose series. Additional doses may enhance vaccine effectiveness and help provide broad coverage against emerging SARS-CoV-2 variants. Continued investigation of vaccines and dosing regimens will help refine approaches to help protect this vulnerable subpopulation from COVID-19.