It is well known that basing phylogenetic reconstructions on uncorrected genetic distances can lead to errors in their reconstruction. Nevertheless, it is often common practice to report simply the most similar BLAST (Altschul et al. 1997) hit in genomic reports that discuss many genes (Ruepp et al. 2000; Freiberg et al. 1997). This is because BLAST hits can provide a rapid, efficient, and concise analysis of many genes at once. These hits are often interpreted to imply that the gene is most closely related to the gene or protein in the databases that returned the closest BLAST hit. Though these two may coincide, for many genes, particularly genes with few homologs, they may not be the same. There are a number of circumstances that can account for such limitations in accuracy (Eisen 2000). We stress here that genes appearing to be the most similar based on BLAST hits are often not each others closest relative phylogenetically. The extent to which this occurs depends on the availability of close relatives present in the databases. As an example we have chosen the analysis of the genomes of a crenarcheaota species Aeropyrum pernix, an organism with few close relatives fully sequenced, and Escherichia coli, an organism whose closest relative, Salmonella typhimurium, is completely sequenced.