Over the past 20 years, the development of subtilisins as typical detergent proteases has employed all the tools of enzyme technology, resulting in a constant flow of new and improved enzymes. The number of molecules identified and characterized, however, is in clear opposition to the number of molecules that are entering the market. Will the next-generation detergent proteases be based on new backbones different from subtilisins, or will the use of all available technologies (rational design, directed evolution and exploitation of natural diversity) yield improved subtilisins, ending the current era dominated by high alkaline subtilisins? These questions will have to be answered not only by the performance of the molecules themselves, but also by their yield in fermentation and their compatibility with existing production technologies.