Refining the chemical toolbox to be fit for educational and practical purpose for drug discovery in the 21st Century.

•The purpose of this paper is to contribute to the discussion about medicinal chemistry modernisation.•To rise to the challenges in the 21st Century there is a necessity to refine the chemical toolbox.•Medicinal chemistry taught in academia in the 21st Century must be fit for purpose.•To meet the healthcare challenges of the 21st Century we might have to learn how to ‘work in the dark’.•Computational and DOS approaches to search for new chemical space could lead to smarter NCEs.