Constitutive heterochromatin in mammals is essentially found at centromeres, which are key chromosomal elements that ensure proper chromosome segregation. These regions are considered to be epigenetically defined, given that it is not sequence composition but chromatin organization that defines centromere function. How such an epigenetically defined domain, like the centromere, can be established during development and maintained during somatic cell life are fundamental questions. This review discusses the most recent insights into centromeric heterochromatin organization and replication. We further highlight the plasticity of this domain by describing the large-scale re-organization that occurs during development.