Non-coding RNAs (ncRNAs) represent key molecular players in biological processes and human disease. Several ncRNA types have been discovered including microRNAs (miRNAs) of around 23 nucleotides and long non-coding RNAs (lncRNAs) that are above 200 nucleotides in length. One of the first functional ncRNAs discovered was the lncRNA named X inactive specific transcript (XIST). XIST is the main actor in a fundamental process called X chromosome inactivation (XCI) where, in females, one of the two X chromosomes is silenced to balance the extra gene expression dosage. In this book chapter, we present the emerging evidence for the importance of XCI in diseases such as gastric and bladder cancer and genetic pathologies such as Klinefelter (47,XXY) and Turner (45,X0) syndromes. Furthermore, a new role for the crosstalk between XIST and miRNAs is discussed. Finally, new evidence for sex bias of XCI in human tissues and development of cancer is presented.