Since the beginning of the last century, genetic research has been preoccupied with the dosage compensation question: What mechanism controls equal expression of chromosome X genes between females and males? In the 1950s, many discoveries occurred in the field of cytogenetics related to the sex chromatin of female mammals. Concomitantly, genetic information accumulated with regard to expression patterns of X-linked genes in female mice and the expression effect of translocations between chromosome X and autosomes. In addition, many case reports were published about families with sex-linked diseases. The lately deceased scientist Mary F. Lyon suggested a unifying theory of these findings. In her articles "Gene action in the X-chromosome of the mouse (Mus musculus L.T in 1961, and "Sex chromatin and gene action in the mammalian X-chromosome" in 1962, she suggested that: (1) the heteropyknotic chromosome X was genetically inactivated, (2) the inactivated chromosome X could be either paternal or maternal in origin in different cells of the same animal, and (3) the inactivation occurred early in embryonic development. This theory led to an immediate breakthrough in understanding the basic mechanisms responsible for X-linked diseases and solved many unexplained case studies. Moreover, the inquiry of the mechanism of the phenomenon promoted scientific understanding of a wide range of areas in molecular biology such as DNA methylation, the silencing mechanism by XIST, histone modifications, DNA replication timing and more. The current article deals with some biographical details about Mary F. Lyon, the background of her theory, her historical articles and the development of the field since.