question: Coronavirus disease 2019 (COVID-19) accounts for over 180,000 deaths in the USA. Although COVID-19 affects all racial ethnicities, non-Hispanic Blacks have the highest mortality rates. Evidence continues to emerge, linking the disproportion of contagion and mortality from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a result of adverse social determinants of health. Yet, genetic predisposition may also play a credible role in disease transmission. SARS-CoV-2 enters cells by interaction between SARS-CoV-2 spike protein and the receptor molecule angiotensin converting enzyme 2 (ACE2) expressed on the surface of the target cells, such that polymorphisms and the expression level of ACE2 influence infectivity and consequent pathogenesis of SARS-CoV-2. Genetic polymorphisms in other multiple genes, such as acetylcholinesterase (AChE) and interleukin-6, are also closely associated with underlying diseases, such as hypertension and type 2 diabetes mellitus, which substantially raise SARS-CoV-2 mortality. However, it is unknown how these genetic polymorphisms contribute to the disparate mortality rates, with or without underlying diseases. Of particular interest is the potential that genetic polymorphisms in these genes may be influencing the disparity of COVID-19 mortality rates in Black communities. Here, we review the evidence that biological predisposition for high-risk comorbid conditions may be relevant to our ability to fully understand and therefore address health disparities of COVID-19 deaths in Blacks. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40615-020-00871-y) contains supplementary material, which is available to authorized users.