Stem cells have the inherent capacity to self-renew for an indefinite period of time. This feature is mainly influenced by several major factors, including their environment or culture conditions and the intricate organization of their nuclear material. The nucleus serves as the main regulatory system consisting of chromatin that undergoes a wide range of modifications at the transcriptional, as well as epigenetic, levels, resulting in cellular differentiation. Advances in genetic technologies have helped to refine the description of genome organization at a higher level of resolution, thus fostering a better understanding and appreciation of nuclear organization in relation to self-renewal and differentiation.