Background With over 3,500 species encompassing a diverse range of morphologies and ecologies, snakes make up 36% of squamate diversity. Despite several attempts at estimating higher- level snake relationships and numerous assessments of generic- or species-level phyloge- nies, a large-scale species-level phylogeny solely focusing on snakes has not been com- pleted. Here, we provide the largest-yet estimate of the snake tree of life using maximum likelihood on a supermatrix of 1745 taxa (1652 snake species + 7 outgroup taxa) and 9,523 base pairs from 10 loci (5 nuclear, 5 mitochondrial), including previously unsequenced gen- era (2) and species (61). Results Increased taxon sampling resulted in a phylogeny with a new higher-level topology and cor- roborate many lower-level relationships, strengthened by high nodal support values (> 85%) down to the species level (73.69% of nodes). Although the majority of families and subfamilies were strongly supported as monophyletic with > 88% support values, some families and numerous genera were paraphyletic, primarily due to limited taxon and loci sampling leading to a sparse supermatrix and minimal sequence overlap between some closely-related taxa. With all rogue taxa and incertae sedis species eliminated, higher-level relationships and support values remained relatively unchanged, except in five problematic clades. Conclusion Our analyses resulted in new topologies at higher- and lower-levels; resolved several previ- ous topological issues; established novel paraphyletic affiliations; designated a new sub- family, Ahaetuliinae, for the genera Ahaetulla, Chrysopelea, Dendrelaphis, and Dryophiops; PLOS ONE | DOI:10.1371/journal.pone.0161070 September 7, 2016 1 / 31 a11111 OPEN ACCESS