Although the development and increasingly widespread availability of effective and safe vaccines provides the greatest hope for the future recovery from the increasingly devastating COVID-19 pandemic, there are other preventive efforts that offer an immediate route to decreasing morbidity and mortality. Genomic surveillance is emerging as a vital necessity to achieve effective mitigation and containment. Since SARS-CoV-2 variants have already been detected, it is crucial to obtain reliable evidence about whether they are more contagious, virulent, or more resistant to the available COVID-19 vaccines well before they spread throughout the world. Genomic surveillance leverages applications of next-generation sequencing, creates the availability of whole genome data, and advances phylogenetic methods. These methods offer novel means to detect variants that are phenotypically or antigenically different. Genomic surveillance will facilitate greater early anticipation as well as initiation of effective strategies to mitigate and contain outbreaks of SARS-CoV-2 variants and other novel viruses.