The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the current pandemic, coronavirus disease 2019 (COVID-19). While all people are susceptible to the SARS-CoV-2 infection, the nature and severity of the disease vary significantly among individuals and populations. Importantly, reported disease burdens and case fatality rates differ considerably from country to country. There are, however, still uncertainties about the severity of the disease among individuals or the reason behind a more severe disease in some cases. There is a strong possibility that the severity of this disease depends on a complicated interaction between the host, virus, and environment, which leads to different clinical outcomes. The objective of this article is to point out the essential influential factors related to the host, virus, and environment affecting the clinical outcome of COVID-19.