The compensation of the different level of transcripts of X-linked genes in male and female mammals is achieved through X chromosome inactivation, a complex process that differentially regulates the sex chromosomes of female cells. This mechanism has been dissected at evolutionary, genetic and molecular levels: here, we discuss some of the latest examples that illustrate better these intricate connections, focusing particularly on the emerging role of spatial and three-dimensional chromatin arrangements in the building of this special chromosome, the inactive X chromosome.