Adenoviruses cause a number of self-limiting but often highly infectious diseases that affect multiple organs, most commonly those associated with respiratory, genitourinary and gastrointestinal tracts and the ocular surface. Many factors have driven a search for effective topical and systemic antivirals to adenoviruses. These include patient morbidity, economic losses and chronic visual disturbances associated with epidemic keratoconjunctivitis; and the startling recent trend of high morbidity and rising mortality associated with systemic adenoviral infections in the immunosuppressed, particularly paediatric bone marrow transplant recipients. The development of effective antivirals has proven to be a complex task, owing to the fact that multiple and often genetically divergent adenovirus serotypes can cause similar diseases. Currently, there remains no licensed systemic or topical treatment in the USA or Europe. However, many compounds have been explored for activity against adenoviruses, and some have been evaluated clinically in either a topical setting for ocular disease or in the setting of systemic treatment in the face of life-threatening adenovirus infections. This article outlines such compounds, discusses the potential for their clinical development, and highlights some problems that may be faced in evaluating their efficacy clinically.