More than 130 acyclic purine and pyrimidine nucleoside derivatives have been synthesized. Structure-activity relationships among a selected group of 6- and 9-substituted guanine derivatives will be discussed. By introduction of secondary aliphatic (e.g. isopropyl or secondary butyl) ether groups into acyclic nucleosides such as aciclovir and ganciclovir new lipophilic prodrugs with modified physical and improved pharmacokinetic properties have been obtained. Several compounds with isopropylether groups in the side-chain and/or in the 6-position (among these the 6-deoxy derivative Hoe 602) of the purine moiety displayed excellent antiviral activity when tested in vivo against herpes simplex virus type 1 infection in mice.