The retrometabolic drug design approaches simultaneously incorporate structure activity (SAR) and structure metabolism (SMR) relationships in the design process. Two major approaches were developed, the chemical delivery systems (CDS), which allow chemical-enzymatic targeting of drugs via strategic sequential enzymatic activation of the inactive CDSs. On the opposite end of the retrometabolic design loop are the soft drugs (SD), which are designed to have highly improved therapeutic indeces by controlling their metabolism, after they achieve their therapeutic role. One of the most successful SD class is the 'inactive metabolite approach', where the design starts from an inactive metabolite of a drug. Its strategic manipulation yields an isosteric/isoelectronic drug analog, which is enzymatically deactivated to the very inactive metabolite at the desired compartment and with controlled rate. Overall, retrometabolic approaches represent a complex collection of chemical-enzymatic means for the design of safer drugs and for their controlled release. Most recent advances involve FDA approval of a soft steroid, as well as the first successful brain targeting of various neuropeptides and their brain-targeted analogs.