Since late 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has resulted in more than 143 million confirmed infections and more than 3 million deaths worldwide (as of publication time). In this article, we discuss current knowledge of immune responses that confer protection to more than 80% of the people who have been infected and possible mechanisms by which the virus escapes immune surveillance in people who develop severe disease and those who die from the disease. We also discuss the differences in the immune responses by which, in most children, the infection results in only mild disease, although causing severe disease in some adults. Understanding these differences in both the innate and adaptive immune responses among these people can lead to the development of biotherapeutic treatment modalities that could modulate immune responses to offer protection against SARS-CoV-2 and block the ability of the virus to cause severe disease or death in humans. [Pediatr Ann. 2021;50(5):e222-e226.].