Targeted enrichment of conserved and ultraconserved genomic elements allows universal collection of phylogenomic data from thousands of species. Prior to downstream inference, data from these types of targeted enrichment studies must undergo pre-processing to assemble contigs from sequence data; identify targeted, enriched loci from the off-target background data; align enriched contigs representing conserved loci to one another; and prepare and manipulate these alignments for subsequent phylogenomic inference. PHYLUCE is an efficient and easy-to-install software package that accomplishes these tasks across hundreds of taxa and thousands of enriched loci.