This review article describes our recent research on (from 2005 to the end of 2012) isolation and identification of natural products, their in vivo metabolites and synthesized derivatives as potential anti-viral agents. Bioactivity assays focused on the inhibition of essential viral enzymes such as HIV protease, HCV protease, and -glucosidase. Bioactive compounds were structurally classified as lignans, triterpenes, chlorogenic acid derivatives and farnesyl hydroquinones. The possible mechanisms of inhibition of a representative triterpene and a farnesyl hydroquinone on HIV-1 protease are discussed. We structurally modified some known triterpenes (betulinic, oleanolic, ursolic and glycyrrhetic acids, panaxadiol, panaxatriol) and chlorogenic acid to identify derivatives with improved inhibitory potency or improved selectivity for viral essential enzymes. Some novel structure-activity relationships (SARs) are also presented in this paper.