Investment in combinatorial chemistry (combichem) in the pharmaceutical industry is being driven by the need for increased efficiency. Results from pioneers in the field have demonstrated where mixture or discrete compound synthesis is useful, and what mixture sizes and compound concentrations are appropriate. To make the techniques of combichem of general utility in drug discovery, a broad range of advances is still required. Conversion of organic chemistry to solid phase conditions is key, as are developments in linkers and resins. Library design methodology requires further development. Combinatorial biosynthesis of focused libraries of natural products holds great promise for capitalising on hardwon natural product leads. Miniaturisation of screens is required to reduce the cost of screening combinatorial libraries. Developments in the processes preceding and following synthesis are required to enable the flow of increased numbers of compounds without new bottlenecks developing. The impact of combinatorial chemistry will be greatly enhanced by synergy with ongoing parallel developments in genetic technologies, screening technologies and bioinformatics.