The sequencing of the genomes of several organisms was the first step in understanding genome organisation, gene function and of course life itself. Until now very much information could be gained by searching for similarities between genes or structures and finding homologies or direct orthologous genes. But with the sequencing data, more and more questions arise, which cannot be answered by simply looking the data. Although the yeast Saccharomyces cerevisiae was the first eukaryotic organism, the genome of which was sequenced, almost 14 years later there are still 900 uncharacterised and 800 dubious genes (26 % at all). The unconventional yeast Yarrowia lipolytica also harbours a high number of genes with unknown function-ca. 2,300 (35 %). One hundred seventy out of 220 Yarrowia lipolytica specific genes with no homology to other yeasts are also uncharacterised, which should carry the "differences" between the yeast species. So far only 50 industrial useful genes were characterised (proteases, lipases, esterases, etc.).Genes or gene products that do not have any known function have to be analysed in a more classical, genetical way. Especially the functions of membrane proteins which are resistant to a lot of investigation steps are only rarely elucidated. The Gpr1 protein of Yarrowia lipolytica is such an example. The function cannot be estimated by finding similarities to other proteins with known function. The more the information and phenotypic effects are available, the more complex the interacting network appears. This chapter will show the ongoing discovery of the function of the Gpr1/FUN34/YaaH protein family. This is especially shown for the Gpr1 protein from Yarrowia lipolytica and its orthologues in Saccharomyces cerevisiae. Here the different and also controversial facts are reviewed and discussed.