Bioisosterism has been in existence as a concept in chemistry for a century, but has only relatively recently been able to be directly applied to challenges in drug discovery using molecular modelling techniques. Here, a brief history of bioisosteres and scaffolds is provided documenting the key observations and scientists who founded this area of chemistry, most notably, Langmuir. Methods to identify bioisosteric pairs will be introduced with a brief overview of some of the widely used approaches in the context of drug discovery. Molecular scaffolds and scaffold hopping, a subset of bioisosterism, will also be covered with a brief history of the molecular scaffold (or chemotype, chemical series) in drug discovery going back to Markush. Objective and invariant algorithms to generate molecular scaffolds will be discussed along with how they have been applied to analysing chemical screening libraries.