More than 3 years have passed since Coronavirus disease 2019 (COVID-19) was declared a global pandemic, yet COVID-19 still severely impacts immunocompromised individuals including those treated with hematopoietic cell transplantation (HCT) and chimeric antigen receptor-T-cell therapies who remain at high risk for severe COVID-19 and mortality. Despite vaccination efforts, these patients have inadequate responses due to immunosuppression, which underscores the need for additional preventive approaches. The optimal timing, schedule of vaccination, and immunological correlates for protective immunity remain unknown. Antiviral therapies used early during disease can reduce mortality and severity due to COVID-19. The combination or sequential use of antivirals could be beneficial to control replication and prevent the development of treatment-related mutations in protracted COVID-19. Despite conflicting data, COVID-19 convalescent plasma remains an option in immunocompromised patients with mild-to-moderate disease to prevent progression. Protracted COVID-19 has been increasingly recognized among these patients and has been implicated in intra-host emergence of SARS-CoV-2 variants. Finally, novel SARS-CoV2-specific T-cells and natural killer cell-boosting (or -containing) products may be active against multiple variants and are promising therapies in immunocompromised patients.