With the recent interest on green chemistry, the scientists have focused on developing new and more efficiient solvents to carry out enzymatic-catalyzed reactions with emphasis on reduced costs, risks and toxicity while improving biodegradability. Among the new available solvents, the multimolecular-based liquids (such as ionic liquids and eutectic solvents) have been the subject of most recent studies. Currently, and mainly due to its environmental and economic features, DES are arousing much interest and curiosity. Regarding the biotransformations with lipases, the so-called “lipophilization” reactions are of major interest. However, they are complex to implement mainly because it is difficult to find a suitable reaction medium. Thus, this review aimed at providing a presentation of these multimolecular- based solvents with general overview of the recent studies dealing with lipase-catalyzed reactions in DES. In addition, emphasis was placed on their strengths and weaknesses, especially with the perspective to be use as efficient and green medium to implement complex and valuable biotransformation such as lipase-catalyzed lipophilizations.