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 initial release, HPRD has grown to include over 20,000 protein entries and more than 30,000 protein–protein interactions, making it the largest database for literature-derived interactions. It also contains over 8,000 PTMs for human proteins. New features include protein isoforms, enhanced search options, pathway annotations, and integration of the GenProt Viewer, a browser that allows integration of genomic and proteomic information. 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 expanded significantly in the last three years, with over 20,000 protein entries, including 1,587 protein isoforms. The database includes 33,710 unique protein–protein interactions, with experimental evidence derived from in vivo, in vitro, and yeast two-hybrid experiments. PTMs can alter both structure and function of proteins. HPRD contains 8,409 recorded PTMs, including 5,011 phosphorylation events and 1,132 glycosylation events. Updated annotations include 489 nucleolar proteins and 270 secreted proteins. Tissue expression data have also been added for several entries. New features include protein isoforms, enhanced search options, links to pathways, and integration of the 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 population haplotype patterns. Peptide sequences from mass spectrometry are also mapped onto the genomic sequence. 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 become a unique source of curated information for the human proteome and to spur biomedical discoveries based on integration of genomic, transcriptomic, and proteomic data. Future plans include developing a Protein Distributed Annotation System and integrating transcriptomic data into HPRD. 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 initial release, HPRD has grown to include over 20,000 protein entries and more than 30,000 protein–protein interactions, making it the largest database for literature-derived interactions. It also contains over 8,000 PTMs for human proteins. New features include protein isoforms, enhanced search options, pathway annotations, and integration of the GenProt Viewer, a browser that allows integration of genomic and proteomic information. 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 expanded significantly in the last three years, with over 20,000 protein entries, including 1,587 protein isoforms. The database includes 33,710 unique protein–protein interactions, with experimental evidence derived from in vivo, in vitro, and yeast two-hybrid experiments. PTMs can alter both structure and function of proteins. HPRD contains 8,409 recorded PTMs, including 5,011 phosphorylation events and 1,132 glycosylation events. Updated annotations include 489 nucleolar proteins and 270 secreted proteins. Tissue expression data have also been added for several entries. New features include protein isoforms, enhanced search options, links to pathways, and integration of the 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 population haplotype patterns. Peptide sequences from mass spectrometry are also mapped onto the genomic sequence. 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 become a unique source of curated information for the human proteome and to spur biomedical discoveries based on integration of genomic, transcriptomic, and proteomic data. Future plans include developing a Protein Distributed Annotation System and integrating transcriptomic data into HPRD. The database is supported by the National Institutes of Health and the Institute of Bioinformatics.