My group's contributions in the discovery of the cholesterol-lowering statins and of ACE inhibitors for hypertension and more recently our use of privileged structures in the design of G-protein coupled receptor (GPCR) agonists are the subjects of this review. Each of these areas of research have been separately reviewed. In this historical overview, the focus will be on design issues and on the key role of natural products in providing proof of concept rationales and structural leads from which drug candidates and design ideas were evolved.