The recent sequencing of the complete genome of the fruit fly Drosophila melanogaster has yielded about 30% of the predicted genes with no obvious counterparts in other organisms. These rapidly evolving genes remain largely unexplored. Here, we present evidence for a striking variability in an important Drosophila cell cycle regulator encoded by the gene roughex (rux) in closely related fly species. The unusual level of Rux protein variability indicates that there are very low overall constraints on amino acid substitutions. Despite the lack of sequence similarity, certain common features, including the presence of a C-terminal nuclear localization signal and a functionally important N-terminal RXL cyclin-binding motif, exist between Rux and cyclin-dependent kinase inhibitors of the Cip/Kip family. These results indicate that even some genes involved in key regulatory processes in eukaryotes evolve at extremely high rates.