One of the most exciting challenges in human biology is the understanding of how our genome was constructed during evolution. Here we explore the evolutionary history of the low polymorphic human minisatellite MsH42 and its flanking sequences. We show that the evolutionary birth of MsH42 took place within an intron, early in primate lineage evolution, more than 40 MYA. Then, single base-pair changes and duplications/deletions of repeat blocks by mispairing were probably the main forces governing the generation of this minisatellite and its polymorphism throughout primate evolution. Moreover, we detected several phylogenetic footprints at both sides of MsH42. We believe that our findings will contribute to the understanding of low-variability minisatellite evolution.