Bioisosterism, the design of structural motifs that emulate established functionality to effect a biological response, has evolved into a powerful design principle in medicinal chemistry and drug discovery that can be implemented to address issues associated with intrinsic potency and/or a range of developability challenges. While bioisosterism has its origins in the concept of isosterism, which was invoked to explain the similarity of physicochemical properties between molecules with analogous size and shape, the contemporary interpretation of bioisosterism extends well beyond this simple definition to encompass relationships that reflect a recapitulation of biological properties by molecules that can be structurally quite disparate. This article provides a synopsis of established and emerging bioisosteric relationships that are discussed in the context of applications to solving problems in drug discovery and development. Bioisosteres that are described range from the replacement of hydrogen atoms by deuterium or fluorine to more esoteric higher order bioisosteres that convene intricate arrays of functionality. These are considered nonclassical in nature and offer functional mimesis of a range of simple and complex functionalities encompassing exchangeable groups, cyclic/noncyclic substructures capable of mimicking rings, and extends to include drug–water and drug–metal complexes.