We annotated 22 genes on genomic sequences orthologous to the human chromosome 21q22.11 region from twelve vertebrates of diverse clades. Using these annotations, we assessed conservation of protein products and evolutionary selective pressures acting on these genes. We used comparative approaches combined with profile scanning to determine putative transcription factor binding sites in the promoter regions of these genes as well as to determine and characterize multi-species conserved sequences (MCS) found throughout the region. We report variable selection pressures acting on the genes within this region, in particular with an interferon/interleukin 10 gene cluster involved in the immune response whose genes show evidence for being under postitive selection. In addition, an abundance of multi-species conserved sequences in non-coding sequence were detected in this region which point to putative functional elements. Our findings suggest evidence for previously unreported functional elements in the 21q11.22 region of the human genome and provide specific sites of interest as a guide for molecular biologists and geneticists interested in the genes found within this region.