As explained above, tandem duplications pose a hard problem for automatic alignment algorithms. Clusters of such paralogous genes are therefore particularly hard to align. As a real-life example we consider here the Hox gene clusters of vertebrates. Hox genes code for homeodomain transcription factors that regulate the anterior/posterior patterning in most bilaterian animals [26,27]. This group of genes, together with the so-called ParaHox genes, arose early in metazoan history from a single ancestral "UrHox gene" [28]. Their early evolution was dominated by a series of tandem duplications. As a consequence, most bilaterians share at least eight distinct types (in arthropods, and 13 or 14 in chordates), usually referred to as paralogy classes. These Hox genes are usually organised in tightly linked clusters such that the genes at the 5'end (paralogy groups 9–13) determine features at the posterior part of the animal while the genes at the 3'end (paralogy groups 1–3) determine the anterior patterns.