With 74 genera and subgenera and approximately 740 species, Saprininae represent one of the largest subfamilies of Histeridae (Coleoptera: Histeroidea). Here, we present a phylogenetic hypothesis for Saprininae based on comprehensive taxonomic sampling. This is the first phylogenetic study combining molecular and morphological approaches (cytochrome c oxidase subunit 1, 18S ribosomal RNA and 93 morphological characters). As a result, we propose a new classification; five new tribes are erected: Myrmetini Portevin stat. and sens. nov.; Euspilotini Lackner, trib. nov.; Eremosaprinini Lackner, trib. nov.; Saprinini Blanchard, sens. nov.; and Hypocaccini Lackner, trib. nov. Additional nomenclatural acts are as follows: Chelyoxenus Hubbard is downgraded to a subgenus of Geomysaprinus Ross, thus Geomysaprinus (Chelyoxenus) stat. nov., Nessus Reichardt is transferred from a subgenus of Hypocaccus C. Thomson to a subgenus of Hypocacculus Bickhardt, thus Hypocacculus (Nessus) stat. rest. The following taxa Paraphilothis Vienna, Styphrus Motschulsky, Xerosaprinus Wenzel, Lophobregmus Wenzel, Vastosaprinus Wenzel, Auchmosaprinus Wenzel, Hemisaprinus Kryzhanovskij & Reichardt, Reichardtia Wenzel and Australopachylopus Lackner & Leschen are all downgraded into subgenera of Saprinus Erichson. Thus, Saprinus (Paraphilothis) stat. nov., Saprinus (Styphrus) stat. nov., Saprinus (Xerosaprinus) stat. nov., Saprinus (Vastosaprinus) stat. nov., Saprinus (Auchmosaprinus) stat. nov., Saprinus (Lophobregmus) stat. nov., Saprinus (Hemisaprinus) stat. rest., Saprinus (Reichardtia) stat. nov., Saprinus (Australopachylopus) stat. nov. A new genus, Paraxenus Lackner gen. nov., is proposed for the former South African and Namibian members of the genus Pholioxenus Reichardt, with the following new combinations: Paraxenus diasi (Vienna) comb. nov.; Paraxenus eremicola (Thérond) comb. nov.; Paraxenus namibiensis (Vienna) comb. nov.; Paraxenus oleolus (Thérond) comb. nov.; Paraxenus therondi (Olexa) comb. nov.; and Paraxenus uhligi (Mazur) comb. nov. Additionally, based on the analysis of the dispersal patterns, Myrmetini appear to be a bipolar (amphitropical) clade, while Eremosaprinini appear to be exclusive to the Western Hemisphere. Euspilotini are strongly represented in the Western Hemisphere, with only a handful of species known from the Palaearctic/Oriental regions. Saprinini and Hypocaccini are spread worldwide but are poorly represented in South America. The Holarctic (in particular the Nearctic) Region is proposed as the centre of origin of the subfamily around 80 million years ago (Ma). Inquilinism is hypothesised to be the ancestral state for the group, with several subsequent independent shifts in life histories. Saprininae cladogenesis occurred mainly during the Palaeogene (66–23.03 Ma) and could be linked to the diversification of mammals.