We have previously reported a gene Tdpoz1 (previously called 2cpoz56) that is temporally expressed in unfertilized eggs and in early embryos of the mouse. The putative TDPOZ1 protein carries a tumor necrosis factor receptor-associated factor (TRAF) domain (TD) and a POZ/BTB domain. On the analysis of nine bacterial artificial chromosome (BAC) clones, we have uncovered four more Tdpoz1 homologs in the mouse genome, designated Tdpoz2 through Tdpoz5. Tdpoz1 and Tdpoz2 are found 30 kb apart in a fully sequenced BAC clone (GenBank accession number AF545858). The genes are intronless in the coding region and each carries an intron in the 5′-untranslated region as in other early embryonic genes. The Tdpoz gene cluster is mapped on chromosome 3 at 3F2.1–2.2. RT-PCR experiments and a search of expressed sequence tag (EST) databases show that the Tdpoz1–5 genes are transcribed in early embryos, particularly at the two-cell stage. Exhaustive database searches have further uncovered three more mouse Tdpoz homologs in chromosomes 3 and 11 and 25 other Tdpoz-like orthologs in the genomes of other animal and plant species including human, rat, C. elegans, Drosophila, Arabidopsis and rice. In the rat genome, eight rat Tdpoz genes are found as a cluster in chromosome 2. Hence, TDPOZ proteins form a new protein family on the basis of similar protein domain organization. Based on reported characteristics of known TD- and POZ-bearing proteins, we speculate that TDPOZ proteins may be nuclear scaffold proteins probably involved in transcription regulation in early development and other cellular processes.