Abstract Summary SpacePHARER (CRISPR Spacer Phage–Host Pair Finder) is a sensitive and fast tool for de novo prediction of phage–host relationships via identifying phage genomes that match CRISPR spacers in genomic or metagenomic data. SpacePHARER gains sensitivity by comparing spacers and phages at the protein level, optimizing its scores for matching very short sequences, and combining evidence from multiple matches, while controlling for false positives. We demonstrate SpacePHARER by searching a comprehensive spacer list against all complete phage genomes. Availability and implementation SpacePHARER is available as an open-source (GPLv3), user-friendly command-line software for Linux and macOS: https://github.com/soedinglab/spacepharer. Supplementary information Supplementary data are available at Bioinformatics online.