For the purpose of this chapter, we are going to frame the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through a targeted and simplistic approach. SARS-CoV-2 invades and infects host cells via interaction of its spike protein with mucosal membrane receptor angiotensin-converting enzyme 2 (ACE2). The immune system response can be quite variable and depends on multiple factors, some specific to the virus and others specific to the patient’s immune competence or clinical comorbidities. SARS-CoV-2 can also be unusually effective at evading the triggering of early innate immune responses, such as type 1 interferons and related molecules. It is possible that much of the nature of COVID-19 as an illness is a consequence of this one evasion trick of SARS-CoV-2. In this chapter, we will describe this immune response and discuss mechanisms by which the virus actively seeks to evade our immune system. We will also discuss how we dissect the body’s immune response to assist us in identifying therapeutic and prophylactic targets and with the development of vaccines, and we will look at the effectiveness of these targets on morbidity and mortality and their adverse reaction profiles.