Here we report a novel small protein that is highly conserved across vertebrates. The protein, which we have named TRIQK, has no homology to any previously reported proteins or functional domains, but all vertebrate homologs of this protein share a characteristic triple repeat of the sequence QXXK/R, as well as a hydrophobic C-terminal region. The Xenopus triqk gene (xTriqk) was isolated in an expression screen on the basis of its ability to cause dramatic changes in cell size and nuclear size and morphology in developing embryos. The Xenopus and mouse triqk genes are broadly expressed throughout embryogenesis, and mtriqk is also generally expressed in mouse adult tissues. TRIQK proteins are localized to the endoplasmic reticulum membrane. Depletion of endogenous xTRIQK protein in Xenopus embryos causes no detectable morphological or functional changes in tadpoles.