Natural products have long been regarded as excellent sources for drug discovery given their structure diversity and wide variety of biological activities. Phenylethanoid glycosides are naturally occurring compounds of plant origin and are structurally characterized with a hydroxyphenylethyl moiety to which a glucopyranose is linked through a glycosidic bond. To date several hundred compounds of this type have been isolated from medicinal plants and further pharmacological studies in vitro or in vivo have shown that these compounds possess a broad array of biological activities including antibacterial, antitumor, antiviral, anti-inflammatory, neuro-protective, antioxidant, hepatoprotective, immunomodulatory, and tyrosinase inhibitory actions. Given their extensive activity profile, structure-activity relationships analyses of these compounds have been performed in a number of studies to reveal potential leads for future drug design. This article will summarize the major developments in phenylethanoid glycosides-based research in the past decade. The progresses made in phytochemistry and biological activity studies of these compounds will be reviewed. Particular attention will be given to the novel structures identified to date and the prominent therapeutic values associated with these molecules.