Widespread vaccination, hybrid immunity, and reduced pathogenicity with circulating Omicron variants have decreased the rate of severe coronavirus disease 2019 (COVID-19) outcomes in the general population. Certain patients with COVID-19 remain at high risk for severe outcomes. Clinicians must individualize treatments based on expected benefits and relative harms for patients with mild-to-moderate COVID-19. Guideline-directed therapy for severe and critical COVID-19 has remained static over the last couple of years. Data on immunomodulatory agents have improved our understanding of the management of severe and critical COVID-19, yet uncertainty remains on the role and timing of these agents in the Omicron era.