The Human Protein Reference Database (HPRD) was developed to serve as a comprehensive collection of protein features, post-translational modifications (PTMs), and protein–protein interactions. Since its original report, the database has expanded to over 20,000 protein entries and has become the largest database for literature-derived protein–protein interactions (>30,000) and PTMs (>8000) for human proteins. New features include protein isoforms, enhanced search options, linking of pathway annotations, and integration of a novel browser, GenProt Viewer. With continued support from the biomedical community, HPRD is expected to become a unique source of curated information for the human proteome and to spur biomedical discoveries based on the integration of genomic, transcriptomic, and proteomic data. HPRD provides extensive information on human proteins, including domain architecture, protein functions, protein–protein interactions, PTMs, enzyme–substrate relationships, subcellular localization, tissue expression, and disease association. The database has greatly expanded the number of protein entries, protein–protein interactions, and PTMs. Additional query options, such as BLAST, and browse options have been incorporated. New features include protein isoforms, links to signal transduction pathways, and integration of GenProt Viewer, a novel browser that allows integration of genomic and proteomic information. HPRD currently contains over 20,000 protein entries, including 1587 protein isoforms. It has grown significantly in size over the last three years. The database includes 33,710 unique protein–protein interactions, with experimental evidence derived from in vivo, in vitro, and yeast two-hybrid experiments. PTMs have been enriched, with 8409 recorded PTMs, including 5011 phosphorylation events and 1132 glycosylation events. Updated annotations include 489 nucleolar proteins and 270 secreted proteins. Tissue expression data have been added to a number of entries. New features include protein isoforms, enhanced search options, links to pathways, and integration of GenProt Viewer. The GenProt Viewer provides an integrated genomic, transcriptomic, and proteomic view of the human genome. It includes genomic annotations, transcriptomic data, and integrates Haploview for investigating population haplotype patterns. Experimentally derived peptide sequences are mapped onto the genomic sequence in GenProt Viewer. HPRD data are available for download in XML and tab-delimited formats. Interaction datasets are provided in PSI-MI format. The database is expected to continue to grow and integrate more data, including transcriptomic data and gene expression patterns. The authors encourage users to visit the FAQs page to understand the annotation procedure and philosophy. The database is supported by the National Institutes of Health and the Institute of Bioinformatics.The Human Protein Reference Database (HPRD) was developed to serve as a comprehensive collection of protein features, post-translational modifications (PTMs), and protein–protein interactions. Since its original report, the database has expanded to over 20,000 protein entries and has become the largest database for literature-derived protein–protein interactions (>30,000) and PTMs (>8000) for human proteins. New features include protein isoforms, enhanced search options, linking of pathway annotations, and integration of a novel browser, GenProt Viewer. With continued support from the biomedical community, HPRD is expected to become a unique source of curated information for the human proteome and to spur biomedical discoveries based on the integration of genomic, transcriptomic, and proteomic data. HPRD provides extensive information on human proteins, including domain architecture, protein functions, protein–protein interactions, PTMs, enzyme–substrate relationships, subcellular localization, tissue expression, and disease association. The database has greatly expanded the number of protein entries, protein–protein interactions, and PTMs. Additional query options, such as BLAST, and browse options have been incorporated. New features include protein isoforms, links to signal transduction pathways, and integration of GenProt Viewer, a novel browser that allows integration of genomic and proteomic information. HPRD currently contains over 20,000 protein entries, including 1587 protein isoforms. It has grown significantly in size over the last three years. The database includes 33,710 unique protein–protein interactions, with experimental evidence derived from in vivo, in vitro, and yeast two-hybrid experiments. PTMs have been enriched, with 8409 recorded PTMs, including 5011 phosphorylation events and 1132 glycosylation events. Updated annotations include 489 nucleolar proteins and 270 secreted proteins. Tissue expression data have been added to a number of entries. New features include protein isoforms, enhanced search options, links to pathways, and integration of GenProt Viewer. The GenProt Viewer provides an integrated genomic, transcriptomic, and proteomic view of the human genome. It includes genomic annotations, transcriptomic data, and integrates Haploview for investigating population haplotype patterns. Experimentally derived peptide sequences are mapped onto the genomic sequence in GenProt Viewer. HPRD data are available for download in XML and tab-delimited formats. Interaction datasets are provided in PSI-MI format. The database is expected to continue to grow and integrate more data, including transcriptomic data and gene expression patterns. The authors encourage users to visit the FAQs page to understand the annotation procedure and philosophy. The database is supported by the National Institutes of Health and the Institute of Bioinformatics.