The HMMER web server, accessible at http://hmmer.janelia.org, offers interactive sequence similarity searches using probabilistic methods. The server, designed to overcome the computational limitations of previous versions, provides efficient profile hidden Markov model (profile HMM) searches with a 100-fold speed improvement compared to earlier HMMER versions. It supports searching single protein sequences, multiple protein alignments, or profile HMMs against target sequence databases, as well as protein sequences against the Pfam database. The web server is optimized for various user expertise levels and allows batch uploading of multiple queries. All search methods are also available as RESTful web services, enabling integration into local workflows. The server focuses on minimizing search times and providing intuitive graphical summaries of results, including alignment details and taxonomic distribution. Future improvements aim to reduce search times to near-real-time levels and enhance result visualization, particularly for large-scale searches with numerous hits.The HMMER web server, accessible at http://hmmer.janelia.org, offers interactive sequence similarity searches using probabilistic methods. The server, designed to overcome the computational limitations of previous versions, provides efficient profile hidden Markov model (profile HMM) searches with a 100-fold speed improvement compared to earlier HMMER versions. It supports searching single protein sequences, multiple protein alignments, or profile HMMs against target sequence databases, as well as protein sequences against the Pfam database. The web server is optimized for various user expertise levels and allows batch uploading of multiple queries. All search methods are also available as RESTful web services, enabling integration into local workflows. The server focuses on minimizing search times and providing intuitive graphical summaries of results, including alignment details and taxonomic distribution. Future improvements aim to reduce search times to near-real-time levels and enhance result visualization, particularly for large-scale searches with numerous hits.