This review summarizes key virological parameters of SARS-CoV-2, the clinical spectrum of COVID-19, antiviral options, resistance, and the evolution of SARS-CoV-2 during the first four years of the pandemic. It draws on evidence that has been continuously updated throughout the pandemic by the interdisciplinary working group ‘SARS-CoV-2 Diagnostics and Evolution’ at Robert Koch Institute (RKI), Germany’s national public health institute. We describe basic SARS-CoV-2 characteristics and highlight notable virus variants from 2020 to mid-2023. During this period, the nationwide collection of SARS-CoV-2 genomes provided a substantial resource for monitoring viral lineage frequencies and mutations. We summarize this dataset to underscore the importance of virological surveillance in the context of public health and pandemic preparedness.