This chapter discusses the most well-known click reaction the copper-catalyzed azide-alkyne cycloaddition (CuAAC), as well as ruthenium-catalyzed process (RuAAC). It also discusses a selection of click reactions that are orthogonal to CuAAC and RuAAC. However, these are not necessarily catalytic; they can be used in concert with their catalytic counterparts, allowing for the synthesis of a large variety of complex molecular structures. In CuAAC reactions, ligands protect Cu (I) from disproportionation and oxidation due to the presence of oxygen and other oxidizing species. Ligands may also activate the Cu atom for productive interaction with the alkyne and azide and promote the transition-state complex by substrate binding. Another efficient, transition-metal-mediated click reaction is the versatile Cu (I)-catalyzed nitroxide radical coupling (NRC) with an alkyl halide. Macro-molecular ligands derivatized with 2, 2, 6, 6-tetramethylpiperidine-oxyl (TEMPO) can be coupled with alkyl halides using a Cu bromide-ligand catalyst at elevated temperatures.