Coronavirus disease 2019 (COVID-19) has had profound effects on the health of individuals and on healthcare systems worldwide. While healthcare workers on the frontlines have fought to quell multiple waves of infection, the efforts of the larger research community have changed the arch of this pandemic as well. This review will focus on biomarker discovery and other efforts to identify features that predict outcomes, and in so doing, identify possible effector and passenger mechanisms of adverse outcomes. Identifying measurable soluble factors, cell-types, and clinical parameters that predict a patient's disease course will have a legacy for the study of immunologic responses, especially stimuli, which induce an overactive, yet ineffectual immune system. As prognostic biomarkers were identified, some have served to represent pathways of therapeutic interest in clinical trials. The pandemic conditions have created urgency for accelerated target identification and validation. Collectively, these COVID-19 studies of biomarkers, disease outcomes, and therapeutic efficacy have revealed that immunologic systems and responses to stimuli are more heterogeneous than previously assumed. Understanding the genetic and acquired features that mediate divergent immunologic outcomes in response to this global exposure is ongoing and will ultimately improve our preparedness for future pandemics, as well as impact preventive approaches to other immunologic diseases.