Genome sequences from several blood borne and respiratory viruses have recently been recovered directly from clinical specimens by variants of a technique known as sequence-independent single primer amplification. This and related methods are increasingly being used to search for the causes of diseases of presumed infectious aetiology, but for which no agent has yet been found. Other methods that do not require prior knowledge of the genome sequence of any virus that may be present in the patient specimen include whole genome amplification, random PCR and subtractive hybridisation and differential display. This review considers the development and application of these techniques. Copyright © 2006 John Wiley & Sons, Ltd.