Since our review in Current Organic Chemistry in 1997 (Curr. Org. Chem. 1997, 1, p. 307-344), important advances have been made in the field of natural products antiviral research. Therefore, we provide here a comprehensive review of the latest developments on plant substances as antiviral agents. The review is mainly focused on plant-derived substances with an anti-human immunodeficiency virus (anti-HIV) and an anti-herpes simplex virus (anti-HSV) activity. The anti-HIV activity of the plant substances is discussed according to their mechanism of action, targeting the critical steps of the HIV replicative cycle, i.e. adsorption, virus-cell fusion, virus uncoating, reverse transcription, integration, proviral DNA transcription, transcription, translation, assembly, and budding. Some of the anti-HIV active compounds show also immune stimulating properties, which can provide an additional benefit in the treatment of AIDS. The anti-HSV activities of the plant substances are discussed according to their in vitro and in vivo activity against HSV-1 and HSV-2, including acyclovir-resistant strains, and where relevant, their activity against cytomegalovirus is mentioned. Finally, the antiviral activities of plant substances against the influenza virus are briefly outlined.