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From various studies it is now clear that in addition to nucleic acids, enediynes also target other biomolecules, the most prominent of which are the proteins. Since a major portion of currently available drug targets are proteins (enzymes and receptors), this aspect of enediyne chemistry has opened a new window for further exploitation. Newer enediyne-based therapeutics targeting proteins may be possible to design. Moreover, the toxicity of the natural enediynes may arise from the non-selective protein cleavages. Substantial progress has been made to understand the nature of interaction between enediynes and proteins. This article is an attempt to discuss the developments in this area.