The concept of orthogonality has been applied to many areas of chemistry, ranging from wave functions to chromatography. But it was Barany and Merrifield's orthogonal protecting group strategy that paved the way for solid phase peptide syntheses, other important classes of biomaterials such as oligosaccharides and oligonucleotides, and ultimately to a term in widespread usage that is focused on chemical reactivity and binding selectivity. The orthogonal protection strategy has been extended to the development of orthogonal activation, and recently the click reaction, for streamlining organic synthesis. The click reaction and its variants are considered orthogonal as the components react together in high yield and in the presence of many other functional groups. Likewise, supramolecular building blocks can also be orthogonal, thereby enabling programmed self-assembly, a superb strategy to create complex architectures. Overall, orthogonal reactions and supramolecular interactions have dramatically improved the syntheses, the preparation of functional materials, and the self-assembly of nanoscale structures.