Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the worst medical emergencies that has hit the world in almost a century. The virus has now spread to a large number of countries/territories and has caused over three million deaths. Evidently, the virus has been mutating and adapting during this period. Significant effort has been spent on identifying these variations and their impact on transmission, virulence and pathogenicity of SARS-CoV-2. Binding of the SARS-CoV-2 spike protein to the angiotensin converting enzyme 2 (ACE2) promotes cellular entry. Therefore, human ACE2 variations could also influence susceptibility or resistance to the virus. A deeper understanding of the evolution and genetic variations in SARS-CoV-2 as well as ACE2 could contribute to the development of effective treatment and preventive measures. Here, we review the literature on SARS-CoV-2 and ACE2 variations and their role in COVID-19.