From REACCS, to MDL ISIS/Host Reaction Gateway, and most recently to MDL Relational Chemistry Server, a new product based on Oracle data cartridge technology, MDL's reaction database management and retrieval systems have undergone great changes. The evolution of the system architecture is briefly discussed. The evolution of MDL reaction substructure search (RSS) algorithms is detailed. This article mainly describes a novel RSS algorithm. This algorithm is based on a depth-first search approach and is able to fully and prospectively use reaction specific information, such as reacting center and atom-atom mapping (AAM) information. The new algorithm has been used in the recently released MDL Relational Chemistry Server and allows the user to precisely find reaction instances in databases while minimizing unrelated hits. Finally, the existing and new RSS algorithms are compared with several examples.