This chapter presents synthesis and antiviral evaluation of broad spectrum, orally active analogs of cidofovir (CDV) and other acyclic nucleoside phosphonates. Esters of cidofovir are synthesized either by linking the alkoxyalkyl-bromides or the alkoxyallkanols to cyclic cidofovir, followed by opening of the ring with base. Alkyl esters may be made by either method. Alkoxyalkyl esters of CDV were synthesized and evaluated in vitro in cells infected with poxviruses, herpesviruses, adenoviruses and a polyoma virus. The hexadecyloxypropyl and octadecyloxypropyl esters of CDV had >100 fold increases in antiviral activity because of increased cell uptake and conversion to the diphosphate. The intracellular half life of CDV diphosphate was 8 days. Structure activity studies showed that alkyl or alkoxyalkyl chains of 20 or 22 atoms gave optimal antiviral activity against poxviruses and herpesviruses. Hexadecyloxypropyl (HDP)CDV and octadecyloxyethyl (ODE)-CDV had broad spectrum activity and were active in vitro against poxviruses, herpesviruses, adenovirus and BK virus, a polyoma virus. HDP-CDV and ODE-CDV were orally bioavailable and were active in lethal models of poxvirus and herpesvirus disease. HDP esters of (S)-HPMPA were unexpectedly active against HIV-1 and the approach appears to be generally applicable to other acyclic nucleoside phosphonates.