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X-chromosome inactivation is the genetic mechanism by which X-linked gene expression is equalized between the male and female genders of all placental mammal species. Given that the probability of mutant X-linked allele expression decreases as a result of the inactivation, it has been proposed that females have biological advantages relative to males. These advantages have grabbed the attention of the scientific community in recent years and have focused it on this topic and its clinical implications. To shed some new light on this intriguing phenomenon, this article reviews the most relevant molecular events involved in this process. These events include the role of Xist, the selection mechanism for future X-chromosome inactivation, the age-related inactivation skewing, and the relationship between inactivation and the emergence of X-linked diseases, possible treatments, and longevity.