VOGDB is a comprehensive database of virus orthologous groups, designed to address the challenges of grouping protein sequences from virus genomes due to their diversity and rapid evolution. The database is multi-layered, progressively grouping viral genes into clusters connected by increasing levels of similarity. The first layer uses pair-wise sequence comparisons, the second layer employs sequence profile alignments, and the third layer utilizes predicted protein structures to find the most remote similarities. VOGDB groups enhance the sensitivity of homology searches for novel genes and improve the prediction of annotations or phylogeny inference. It incorporates both prokaryotic and eukaryotic viruses, allowing for the exploration of evolutionary relationships between these groups. VOGDB is updated with each RefSeq release and is freely available under the CC BY 4.0 license. The database's unique features and comprehensive coverage make it a valuable resource for virus bioinformatics, complementing existing tools and databases in the field.VOGDB is a comprehensive database of virus orthologous groups, designed to address the challenges of grouping protein sequences from virus genomes due to their diversity and rapid evolution. The database is multi-layered, progressively grouping viral genes into clusters connected by increasing levels of similarity. The first layer uses pair-wise sequence comparisons, the second layer employs sequence profile alignments, and the third layer utilizes predicted protein structures to find the most remote similarities. VOGDB groups enhance the sensitivity of homology searches for novel genes and improve the prediction of annotations or phylogeny inference. It incorporates both prokaryotic and eukaryotic viruses, allowing for the exploration of evolutionary relationships between these groups. VOGDB is updated with each RefSeq release and is freely available under the CC BY 4.0 license. The database's unique features and comprehensive coverage make it a valuable resource for virus bioinformatics, complementing existing tools and databases in the field.