A systematic overview is presented of the literature that reports the antifouling (AF) protection of underwater structures via the action of enzymes. The overall aim of this review is to assess the state of the art of enzymatic AF technology, and to highlight the obstacles that have to be overcome for successful development of enzymatic AF coatings. The approaches described in the literature are divided into direct and indirect enzymatic AF, depending on the intended action of the enzymes. Direct antifouling is used when the enzymes themselves are active antifoulants. Indirect antifouling refers to the use of enzymes to release an active biocide with AF activity. For direct AF, several patents have been granted, and a commercial product has been launched. However, the achievement of an efficient broad-spectrum AF coating based on a single or a few enzymes has not yet been achieved. An indirect AF coating is not yet available commercially. The technology is mainly limited by the instability of substrate supply, whether the substrates are found in the surrounding seawater or in the coating itself. Legislative issues regarding which part(s) of an enzyme system should be regarded as biocidal for product registration purposes are also considered. The above question currently remains unanswered for technologies utilising indirect enzymatic AF.