The systematization of species in plant taxonomy based on the phylogenetic relationships among them are of utmost importance and also very challenging in large genera. In those, phylogenetic results often may suggest substantially different relationships than previous classifications, and call for large-scale taxonomic revisions. Delimitation of the genus Silene has been and is still somewhat controversial, and recent molecular phylogenetic studies have settled several monophyletic groups that differ substantially from previous taxonomies. The infrageneric taxonomy of Silene s.str. has not been updated as a whole taking the phylogenetic information into account. In this study, we review previous phylogenetic results based on multiple loci, and conducted comprehensive gene tree analyses based on the nrDNA ITS and cpDNA rps16 regions for 1586 and 944 samples representing 415 and 397 species, respectively, including Silene and its allies, as well as a species tree analysis including 262 samples representing 243 species. We sampled representatives from all 44 sections recognized in the most recent global revision of the genus. The results support the recognition of three subgenera, i.e., S. subg. Behenantha, S. subg. Lychnis and S. subg. Silene, which is partly in agreement with previous molecular phylogenetic findings and contradicts all previous traditional classifications. Silene sect. Atocion, with a few annual species showing a narrow distribution range in the eastern Mediterranean, is treated as incertae sedis because of its uncertain phylogenetic position, possibly due to exceptionally high substitution rates. Silene subg. Lychnis, weakly supported as sister to the other subgenera, splits into three main clades and includes four sections. Silene subg. Behenantha, which forms a possible sister group in relation to S. subg. Silene, is poorly resolved basally and includes a large number of mostly small clades recognized as 18 sections. In S. subg. Silene, 11 sections are recognized, among which four are broadly circumscribed: S. sect. Auriculatae, S. sect. Sclerocalycinae, S. sect. Silene and S. sect. Siphonomorpha. Silene sect. Acutifoliae and S. sect. Portenses are described here as new taxa, whereas new status or new combinations are proposed for S. sect. Anotites, S. sect. Muscipula, S. sect. Petrocoma, S. sect. Pulvinatae, S. sect. Sclerophyllae and S. sect. Uebelinia. Five new combinations and two new names are proposed for taxa in Silene formerly assigned to Lychnis and Uebelinia. The correct infrageneric nomenclature compatible with the new infrageneric system is provided along with synonymy and type citations. Shortcomings of this study, such as the lack of a morphological diagnostic key and sparse sampling of some large sections, are listed and discussed.