The hepatitis C virus (HCV) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemics have caused global morbidity and mortality. The epidemiology of these two viruses differ extensively, but the genomes of both can be studied to improve our understanding of how they spread locally and internationally. Advances in whole genome sequencing technology in the last decade have revolutionized virus epidemiology: virus genomes are now more readily available for analysis and are an important component of virus surveillance and epidemiology. Virus genomes can help discriminate between local transmission and external introductions and they are used to track the evolution of the virus. In this thesis, we used genomic epidemiological methods to provide insights into HCV transmission among men who have sex with men (MSM) and SARS-CoV-2 transmission patterns in Amsterdam. In the first part of this thesis, we show that HCV elimination among MSM could be complicated due to international transmission clusters and propose an HCV genomic surveillance infrastructure. We also highlight that HCV variants resistant to existing therapies are currently not a threat to elimination, but that resistance should be closely monitored. In the second part of this thesis, we utilized similar methods to describe a SARS-CoV-2 outbreak in a nightclub in Amsterdam and to describe SARS-CoV-2 transmission in the Amsterdam University Medical Centers. This thesis concludes by discussing how results from these studies can be used to guide and inform public health action.