Retrometabolic approaches incorporate targeting and metabolic considerations into the drug design process and represent a novel, systematic methodology for the design of safe, localized compounds. Two major design concepts aimed to increase the therapeutic index of drugs were developed. Chemical delivery systems allow targeting of active biological molecules to specific target sites or organs, based on predictable enzymatic activation. Soft drug approaches are used to design new drugs by building in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequent to exerting its biological effects. Many examples are provided; related computer programs are also briefly discussed.