On May 5, 2023, the Director-General of the World Health Organization (WHO) advised the transition to long-term management of the COVID-19 pandemic and that COVID-19 is now an established and ongoing health issue that is no longer a public health emergency of international concern (PHEIC). The WHO decision was based on an analysis of the decreasing trend in mortality, the decline in hospital admissions and Intensive Care Unit (ICU) admissions from COVID-19, and the increasing levels of population immunity to SARS-CoV-2. This Editorial aims to highlight what is known of the factors that drive new variants, subvariants, and lineages of SARS-CoV-2 associated with immune escape to previous infection or vaccines and resistance to antiviral treatments as the end of the COVID-19 pandemic is declared.