The need for antiviral drugs is growing rapidly as more viral diseases are recognized. The methods used to discover antiviral drugs have evolved considerably over the past 40 years and the overall process of discovery can be broken down into subprocesses which include lead generation, lead optimization and lead development. Various methods are now employed to ensure these processes are carried out efficiently. For lead generation, screening methodologies have developed to the extent where hundreds of thousands of compounds can be screened against a particular target. An alternative approach is to use the structures of enzyme substrates as a starting point for drug discovery. Much use is now made of X-ray crystallographic data of target-inhibitor complexes for the optimization of lead structures, and methods for preparing libraries of compounds to assist both generation and optimization of leads are well-developed. The methods used to predict and improve the pharmacokinetic properties of compounds are also changing rapidly. Finally, novel approaches to antiviral therapy using oligonucleotide-based compounds or by modulating the host immune response are also being explored. This review discusses these approaches, provides examples of where their application has been successful and sets them against a historical background.