Implicit in the characterization of a model organism is the hope that insights into its biology can be extended to other species. For this hope to be fulfilled, the phylogenetic position of the model organism within a larger evolutionary framework must be known. We focus here on major model organisms of developmental genetics and cell biology. We first consider the positions of the nematode Caenorhabditis elegans and the arthropod Drosophila melanogaster within a phylogeny of the major advanced metazoan groups. Then we consider the evolutionary relationships between fungi (represented by Saccharomyces cerevisiae and Schizosaccharomyces pombe), plants, and animals. We show, by a direct comparison with small subunit ribosomal RNA (18 S rRNA), that RNA polymerase II is an appropriate molecule for addressing the phylogenetic branchings in the early evolution of eukaryotes. The results from the analyses of newly determined and previously published sequences of the two largest subunits of RNA polymerase II suggest the following. Firstly, that plants and animals share a last common ancestor that excludes fungi, the lineage of which originated earlier. Secondly, that the lineage leading to the nematode Caenorhabditis elegans diverged earlier from the Metazoa than the lineages of arthropods, deuterostomes, annelids and molluscs. Finally, that deuterostomes arose from within protostomes. RNA polymerase II is well-suited for the elucidation of the evolutionary relationships among eukaryotes. We emphasize the implications of our results for other biological disciplines in addition to molecular evolution, as a phylogenetic framework allows predictions and inferences to be made about the existence of fundamental biological mechanisms elucidated in model organisms.