Phylogeny of the TMEM16 protein family: some members are overexpressed in cancer. TMEM16 proteins are found in all eukaryotes and have eight putative transmembrane domains with NH2 and COOH termini located on the luminal side of the vesicle or plasma membrane. Nine homologues exist in humans and mice. Several of the human genes are overexpressed in cancer and could be valuable tumor markers, especially in profiling gene expression with microarrays. In Drosophila, homologues are involved in chromosome separation. In Baker''s yeast, the one homologue is expressed exclusively in the bud and involved in osmotic regulation. In sea urchin embryos, the protein is associated with nuclei. In mammals, the functions of TMEM16 proteins are still unknown. We predict that the TMEM16 proteins will gain importance in the study of normal and malignant tissues. This report presents the first comprehensive phylogeny of TMEM16 proteins. The two phylograms show that these proteins fall into distinct families, which are differentiated from each other in all animal lineages. Here, all previous studies on these proteins are compiled in table form with the hope this compilation will facilitate future work on these genes and their protein products.