Immunocompromised individuals and particularly those with hematologic malignancies are at increased risk for SARS-CoV-2-associated morbidity and mortality due to immunologic deficits that limit prevention, treatment, and clearance of the virus. Understanding the natural history of viral infections in people with impaired immunity due to underlying conditions, immunosuppressive therapy, or a combination thereof has emerged as a critical area of investigation during the COVID-19 pandemic. Studies focused on these individuals have provided key insights into aspects of innate and adaptive immunity underlying both the antiviral immune response and excess inflammation in the setting of COVID-19. This review presents what is known about distinct states of immunologic vulnerability to SARS-CoV-2 and how this information can be harnessed to improve prevention and treatment strategies for immunologically high-risk populations. Vardhana and colleagues discuss how discrete immunological defects in individuals with cancer and other immunosuppressive conditions have informed our understanding of the role of the immune system in protection and toxicity from SARS-CoV-2. They discuss how these immune defects affect the protective impact of vaccination strategies in these individuals and provide insight to limit COVID-19-associated morbidity in this high-risk population.