There is a highly heterogeneous response to infection with SARS-CoV-2 with reports to date suggesting the vast majority of patients are minimally symptomatic, while a significant subset developing life-threatening lung injury associated with hyper-inflammatory response. While initial studies suggested that the cytokine storm was the main driver of lung injuries, more recent observation suggest that vascular lesions leading to severe vasculitis and disseminated intravascular coagulation may also significantly contribute to COVID-19 disease pathophysiology. Regardless of whether the hyperinflammation is causative or reactive, given much of the morbidity and mortality is also associated with hyperinflammation, a better understanding of the immunologic underpinnings of differential responsiveness is necessary to better identify therapeutic targets. Dozens of immunomodulatory agents are rapidly going into clinical trials as well as being used routinely, without a thorough understanding for which inflammatory pathways and cell types to best target, which could be detrimental to critically ill patients. Many of these agents are being tested within the Mount Sinai Health System in New York, a city disproportionately affected by COVID-19. We propose to focus the significant resources of our Human Immune Monitoring Center (HIMC) and the Mount Sinai Cancer Immune Monitoring and Analysis Centers (CIMAC), which have well established and validated platforms to characterize to an unprecedented depth the immune phenotype of SARS-CoV-2 patients at diagnosis and during disease progression with the overarching goal to establish an algorithm to predict disease severity and guide immunomodulatory strategies as well as identify novel immune targets of disease.