This review summarizes the rapidly expanding applications of orthogonal, "click" chemistries in the synthesis and functionalization of soft materials. The focus is on the preparation of functional polymers, modification of two-dimensional polymer surfaces and three-dimensional polymer objects, and the orthogonal modification of biological entities such as peptides, proteins, enzymes, and viral systems. The review highlights the use of robust, efficient, and orthogonal (REO) approaches for the synthesis of well-defined, discrete macromolecules or nanoscale structures. It discusses various REO reactions, including Cu-catalyzed azide/alkyne cycloaddition (CuAAC), thiol-ene, oxime, Diels-Alder, and pyridyl disulfide reactions, as well as examples of Michael additions and activated ester couplings. The review also covers the synthesis of polymers with varying architectures, including linear, graft, star, and branched structures, and the use of controlled polymerization techniques to achieve precise control over polymer properties. The applications of REO chemistry in the synthesis of polymers, nanoparticle functionalization, and the creation of patterned surfaces are discussed. The review emphasizes the importance of REO chemistry in the development of new applications in electronics, biomedicine, and other fields where precise control over functionality is critical. The review also highlights the potential of REO chemistry in the synthesis of complex polymeric topologies and the functionalization of soft materials through orthogonal strategies. The review concludes with the importance of REO chemistry in the development of new materials and techniques for synthesizing large complex molecules with diverse functions and chemical nature.This review summarizes the rapidly expanding applications of orthogonal, "click" chemistries in the synthesis and functionalization of soft materials. The focus is on the preparation of functional polymers, modification of two-dimensional polymer surfaces and three-dimensional polymer objects, and the orthogonal modification of biological entities such as peptides, proteins, enzymes, and viral systems. The review highlights the use of robust, efficient, and orthogonal (REO) approaches for the synthesis of well-defined, discrete macromolecules or nanoscale structures. It discusses various REO reactions, including Cu-catalyzed azide/alkyne cycloaddition (CuAAC), thiol-ene, oxime, Diels-Alder, and pyridyl disulfide reactions, as well as examples of Michael additions and activated ester couplings. The review also covers the synthesis of polymers with varying architectures, including linear, graft, star, and branched structures, and the use of controlled polymerization techniques to achieve precise control over polymer properties. The applications of REO chemistry in the synthesis of polymers, nanoparticle functionalization, and the creation of patterned surfaces are discussed. The review emphasizes the importance of REO chemistry in the development of new applications in electronics, biomedicine, and other fields where precise control over functionality is critical. The review also highlights the potential of REO chemistry in the synthesis of complex polymeric topologies and the functionalization of soft materials through orthogonal strategies. The review concludes with the importance of REO chemistry in the development of new materials and techniques for synthesizing large complex molecules with diverse functions and chemical nature.