By modern definition, dynamic combinatorial chemistry is generally considered to be a method of facilitating the generation of new chemical species by the reversible linkage of simple building blocks, under thermodynamic control. This principle is known to select the most thermodynamically stable product from an equilibrating mixture of a number of components, a concept commonly utilised in synthetic chemistry to direct the control of reaction selectivity. Although this approach was arguably utilised in the work of Fischer and Werner as early as the 19th century, their respective studies of carbohydrate and coordination chemistry were restricted to rudimentary speculation, requiring the rationale of modern thermodynamics. It was not until supramolecular chemistry revealed early concepts of molecular recognition, complementarity and self-organisation that chemists could begin to employ strategies for the rational design and synthesis of macromolecular targets. The concept of template synthesis was further developed and rationalised through the pioneering work of Busch in the 1960s, which clearly defined the role of a metal ion template in stabilising the desired ‘thermodynamic’ product, allowing for its isolation from the complex equilibrating mixture. Although the work of Busch helped to establish the template method as a powerful synthetic route to stable macrocyclic structures, this approach remained exclusively within the domain of inorganic chemistry until the early 1990s, when Sanders et al. first proposed the concept of dynamic combinatorial chemistry. Their work combined thermodynamic templation in tandem with combinatorial chemistry, to generate an ensemble complex porphyrin and imine macrocycles using a modest selection of simple building blocks.
Sanders then developed this early manifestation of dynamic combinatorial chemistry as a strategy for organic synthesis; the first example being the thermodynamically-controlled macrolactonisation of oligocholates to assemble cyclic steroid-derived macrocycles capable of interconversion via component exchange.  Early work by Sanders et al. employed transesterification to generate dynamic combinatorial libraries. In retrospect, it was unfortunate that esters were selected for mediating component exchange, as transesterification processes are inherently slow and require vigorous anhydrous conditions. However, their subsequent investigations identified that both the disulfide and hydrazone covalent bonds exhibit effective component exchange processes and so present a reliable means of generating dynamic combinatorial libraries capable of thermodynamic templation. This chemistry now forms the basis of much research in the developing field of dynamic covalent chemistry, and has in recent years emerged as a powerful tool for the discovery of molecular receptors.