The advent of single cell virology has heralded a new understanding of the diverse outcomes that follow the meeting of a virus and a host cell. While it is clear that both host and viral factors are important in tipping the balance to productive replication following virus entry, much of the current body of work has focused on RNA viruses. We have developed a high throughput imaging utilising recombinant vaccinia viruses (a dsDNA virus) that express fluorescent markers at defined stages of the virus replication cycle. We have characterised the frequency and diversity of outcomes following vaccinia virus infection and examined the role of multiplicity-of-infection, cell cycle, apoptosis and immune signalling in leading to productive replication.