Cytomegalovirus (CMV) is the number one cause of congenital infection. However, no approved vaccine is available in part due to a lack of knowledge on how primary infection becomes established and the dynamics of viral transmission. Using mathematical and mouse infection models, we examined the kinetics of primary infection, determined the drivers of CMV transmission, and tested vaccination strategies. Our results bring insight into the immune correlates of protection, the spatiotemporal dynamics of CMV infection, and the requirements for a successful CMV vaccine.