There are many challenges that have to be faced in using anti-viral drugs, chief among them anti-viral resistance that can commonly occur. Here we have considered new methodologies to finding novel compounds targeting human cytomegalovirus, a major human pathogen for which there are few effective treatments and significant issues surrounding anti-viral drug resistance. This presentation will discuss our use of automated high throughput compound and genetic screens to identify novel anti-HCMV compounds targeting cellular proteins, plus how this data has been used in a machine learning approach to identify novel anti-viral targets. Recent unpublished data on compounds targeting viral DNA will also be discussed, as will the single molecule imaging we have used to understand the mechanism of action of these compounds.