The Hsp90 chaperone is a promising target for the treatment of cancer. Well known inhibitors, e.g. geldanamycin, radicicol, novobiocin and their derivatives, have been extensively investigated and optimized as inhibitors of Hsp90. More recently, new chemotypes of natural origin were reported to modulate Hsp90 function via various and often “non-conventional” mechanisms. This review focuses on these novel classes of natural products whose structures have not yet been thoroughly explored for medicinal chemistry purposes. These novel chemotypes may constitute interesting starting points for future drug discovery campaigns.