Drug monitoring organizations report that new psychoactive substances continue to emerge, posing health and social threats and creating an unprecedented challenge for national and international law systems. By the time a new regulation comes into force, there are already novel drugs ready to be launched into the market. To keep pace with this ever-evolving situation, countries have introduced new types of legal responses such as generic control of substances. Screening large compound collections against these new generic definitions is a challenge for traditional search engines. New approaches like the introduction of novel homology groups and state-of-the-art Markush search technologies are emerging to address these challenges, and this paper gives examples of the successful application of such new technology.