Sand flies infect more than one million people annually with Leishmania parasites and other bacterial and viral pathogens. Progress in understanding sand fly adaptations to xenobiotics, such as insecticides has been hampered by the limited availability of genomic resources. Here we sequenced, assembled and annotated the transcriptomes of 11 phlebotomine sand fly species, and used them to generate new evolutionary insights pertaining to their adaptations to xenobiotics, including those contributing to insecticide resistance. We annotated and performed large-scale phylogenetic comparisons of more than 2,700 sand fly genes from the five major detoxification enzyme families, Cytochrome P450s (CYPs), Glutathione-S-Transferases (GSTs), UDP-Glycosyltransferases (UGTs), Carboxyl/Cholinesterases (CCEs) and ATP-Binding Cassette (ABC) Transporters. This comparative approach uncovered that sand flies have evolved diverse CYP and GST repertoires, with striking expansions in gene groups encoding for potential xenobiotic metabolizers. Furthermore, we identified conserved orthologs for two primary insecticide targets, acetylcholinesterase-1 (Ace1) and Voltage Gated Sodium Channel (VGSC). This work provides novel biological insights and valuable genomic resources for enabling sand fly research in xenobiotic adaptation and insecticide resistance.