This review highlights the rapid expansion of orthogonal, "click" chemistry in the synthesis and functionalization of advanced functional soft materials. The focus is on the preparation and modification of two-dimensional polymer surfaces and three-dimensional polymer objects, as well as the orthogonal modification of biological entities such as peptides, proteins, enzymes, and viral systems. The review covers various aspects of control over individual polymers in solution, the use of REO chemistries for modifying three-dimensional objects, and the exploitation of these chemistries for the orthogonal modification of biological entities. Key REO reactions discussed include Cu-catalyzed azide/alkyne cycloaddition (CuAAC), thiol-ene, oxime, Diels-Alder, and pyridyl disulfide reactions. The review also explores the synthesis and functionalization of polymers with varying architectures, including linear, graft, star, and branched structures, emphasizing the differentiation of regions within macromolecular frameworks. Additionally, it discusses the preparation and functionalization of nanoparticles, the construction of two-dimensional surfaces, and the orthogonal functionalization of biological systems. The importance of REO chemistry in developing robust, efficient, and orthogonal techniques for the synthesis of highly modular materials is emphasized, with applications spanning medical imaging, drug delivery, and energy capture and storage.This review highlights the rapid expansion of orthogonal, "click" chemistry in the synthesis and functionalization of advanced functional soft materials. The focus is on the preparation and modification of two-dimensional polymer surfaces and three-dimensional polymer objects, as well as the orthogonal modification of biological entities such as peptides, proteins, enzymes, and viral systems. The review covers various aspects of control over individual polymers in solution, the use of REO chemistries for modifying three-dimensional objects, and the exploitation of these chemistries for the orthogonal modification of biological entities. Key REO reactions discussed include Cu-catalyzed azide/alkyne cycloaddition (CuAAC), thiol-ene, oxime, Diels-Alder, and pyridyl disulfide reactions. The review also explores the synthesis and functionalization of polymers with varying architectures, including linear, graft, star, and branched structures, emphasizing the differentiation of regions within macromolecular frameworks. Additionally, it discusses the preparation and functionalization of nanoparticles, the construction of two-dimensional surfaces, and the orthogonal functionalization of biological systems. The importance of REO chemistry in developing robust, efficient, and orthogonal techniques for the synthesis of highly modular materials is emphasized, with applications spanning medical imaging, drug delivery, and energy capture and storage.