Highly accurate structure prediction methods are generating an avalanche of publicly available protein structures. Searching through these structures is becoming the main bottleneck in their analysis. Foldseek enables fast and sensitive comparisons of large structure sets. It reaches sensitivities similar to state-of-the-art structural aligners while being four to five orders of magnitude faster. Foldseek is free open-source software available at foldseek.com and as a webserver at search.foldseek.com.Competing Interest StatementThe authors have declared no competing interest.