Base-catalyzed ring-opening reaction of epoxides with the thiol nucleophiles is useful in the preparation and post-polymerization modification of synthetic polymers. Due to its many beneficial characteristics, this process is referred to as the thiol-epoxy 'click' reaction. In this article, our aim is to discuss the fundamental attributes of this process by tracing our own steps in the field. We initially address the aspects of efficiency, regio-selectivity, stoichiometry, and reaction conditions with the help of linear, hyperbranched, graft, dendritic, and cross-linked poly(β-hydroxy thioether)s. A special emphasis is placed on hydrogel synthesis and photopolymerization on surfaces. Subsequently, quenching of the alkoxide anion is considered which is a critical step in the formation of the β-hydroxy thioether linkage upon completion of reaction. The amenability of further reaction on the hydroxy and thioether groups through esterification and sulfur alkylation is then discussed. Initially, post-gelation/fabrication modification of sulfide linkages is considered to obtain cationic sulfonium hydrogels and zwitterionic photopatterned networks with antibacterial and antibiofouling properties, respectively. A post-synthesis functionalization strategy is then described to access same centered and segregated main-chain poly(β-hydroxy sulfonium)s as potent antibacterial materials. In side-chain polysulfides, the sequential post-synthesis modifications involving poly(glycidyl methacrylate) scaffolds can lead to the formation of amphiphilic homopolymers. The application of such materials is discussed in the arena of siRNA delivery. Finally, concerns relating to the formation of disulfide defects and open research goals such as study of the orthogonality of the reaction are addressed.