The centromere has a pivotal role in structuring chromosomal architecture, but remains a poorly understood and seemingly paradoxical "black hole." Centromeres are a very rapidly evolving segment of the genome and it is now known that centromere shifts in evolution are not rare and must be considered on a par with other chromosome rearrangements. Recently, unprecedented findings on neocentromeres and evolutionary new centromeres (ENC) have helped clarify the relationship of the centromere within the genome and shown that these two phenomena are two faces of the same coin. No prominent sequence features are known that promote centromere formation and both types of new centromeres are formed epigenetically, both clinical neocentromeres and ENC cluster at chromosomal "hotspots." The clustering of neocentromeres in 8p is probably the result of the relatively high frequency of noncanonical pairing. Studies on the evolution of the chromosomes 3, 13, and 15 help explain why there are clusters of neocentromeres. These domains often correspond to ancestral inactivated centromeres and some regions can preserve features that trigger neocentromere emergence over tens of millions of years. Neocentromeres may be correlated with the distribution of segmental duplications (SDs) in regions of extreme plasticity that often can be characterized as gene deserts. Further, because centromeres and associated pericentric regions are dynamically complex, centromere shifts may turbocharge genome reorganization by influencing the distribution of heterochromatin. The "reuse" of regions as centromere seeding-points in evolution and in human clinical cases further extends the concept of "reuse" of specific domains for "chromosomal events."