Abstract Summary Standardized interfaces for efficiently accessing high-throughput sequencing data are a fundamental requirement for large-scale genomic data sharing. We have developed htsget, a protocol for secure, efficient and reliable access to sequencing read and variation data. We demonstrate four independent client and server implementations, and the results of a comprehensive interoperability demonstration. Availability and implementation http://samtools.github.io/hts-specs/htsget.html Supplementary information Supplementary data are available at Bioinformatics online.