The male of many animals has one chromosome pair, the sex chromosomes, consisting of unequal members called X and Y. At meiosis the X and Y chromosomes first pair then disjoin and pass to different cells. One-half of the gametes (spermatozoa) formed contain the X chromosome and the other half the Y. The female has two X chromosomes; all egg cells normally carry a single X. The eggs fertilized by X-bearing spermatozoa give females (XX), and those fertilized by Y-bearing spermatozoa give males (XY).

The genes located in the X chromosomes exhibit what is known as sex-linkage or crisscross inheritance. This is because of a crucial difference between the paired sex chromosomes and the other pairs of chromosomes (called autosomes). The members of the autosome pairs are truly homologous; that is, each member of a pair contains a full complement of the same genes (albeit, perhaps, in different allelic forms). The sex chromosomes, on the other hand, do not constitute a homologous pair, as the X chromosome is much larger and carries far more genes than does the Y. Consequently, many recessive alleles carried on the X chromosome of a male will be expressed just as if they were dominant, for the Y chromosome carries no genes to counteract them. The classic case of sex-linked inheritance, described by Morgan in 1910, is that of the white eyes in Drosophila. White-eyed females crossed to males with the normal red eye colour produce red-eyed daughters and white-eyed sons in the F₁ generation and equal numbers of white-eyed and red-eyed females and males in the F₂ generation. The cross of red-eyed females to white-eyed males gives a different result: both sexes are red-eyed in F₁ and the females in the F₂ generation are red-eyed, half the males are red-eyed, and the other half white-eyed. As interpreted by Morgan, the gene that determines the red or white eyes is borne on the X chromosome, and the allele for red eye is dominant over that for white eye. Since a male receives its single X chromosome from his mother, all sons of white-eyed females also have white eyes. A female inherits one X chromosome from her mother and the other X from her father. Red-eyed females may have genes for red eyes in both of their X chromosomes (homozygotes), or they may have one X with the gene for red and the other for white (heterozygotes). In the progeny of heterozygous females, one-half of the sons will receive the X chromosome with the gene for white and will have white eyes, and the other half will receive the X with the gene for red eyes. The daughters of the heterozygous females crossed with white-eyed males will have either two X chromosomes with the gene for white—and hence have white eyes—or one X with the gene for white and the other X with the gene for red and will be red-eyed heterozygotes.

In humans, red-green colour blindness and hemophilia are among many traits showing sex-linked inheritance and are consequently due to genes borne in the X chromosome.

In some animals—birds, butterflies and moths, some fish, and at least some amphibians and reptiles—the chromosomal mechanism of sex determination is a mirror image of that described above. The male has two X chromosomes and the female an X and Y chromosome. Here the spermatozoa all have an X chromosome; the eggs are of two kinds, some with X and others with Y chromosomes, usually in equal numbers. The sex of the offspring is then determined by the egg rather than by the spermatozoon. Sex-linked inheritance is altered correspondingly. A male homozygous for a sex-linked recessive trait crossed to a female with the dominant one gives, in the F₁ generation, daughters with the recessive trait and heterozygous sons with the corresponding dominant trait. The F₂ generation has recessive and dominant females and males in equal numbers. A male with a dominant trait crossed to a female with a recessive trait gives uniformly dominant F₁ and a segregation in a ratio of 2 dominant males : 1 dominant female : 1 recessive female.

Observations on pedigrees or experimental crosses show that certain traits exhibit sex-linked inheritance; the behaviour of the X chromosomes at meiosis is such that the genes they carry may be expected to exhibit sex-linkage. This evidence still failed to convince some skeptics that the genes for the sex-linked traits were in fact borne in certain chromosomes seen under the microscope. An experimental proof was furnished in 1916 by American geneticist Calvin Blackman Bridges. As stated above, white-eyed Drosophila females crossed to red-eyed males usually produce red-eyed female and white-eyed male progeny. Among thousands of such “regular” offspring, there are occasionally found exceptional white-eyed females and red-eyed males. Bridges constructed the following working hypothesis. Suppose that, during meiosis in the female, gametogenesis occasionally goes wrong, and the two X chromosomes fail to disjoin. Exceptional eggs will then be produced, carrying two X chromosomes and eggs carrying none. An egg with two X chromosomes coming from a white-eyed female fertilized by a spermatozoon with a Y chromosome will give an exceptional white-eyed female. An egg with no X chromosome fertilized by a spermatozoon with an X chromosome derived from a red-eyed father will yield an exceptional red-eyed male. This hypothesis can be rigorously tested. The exceptional white-eyed females should have not only the two X chromosomes but also a Y chromosome, which normal females do not have. The exceptional males should, on the other hand, lack a Y chromosome, which normal males do have. Both predictions were verified by examination under a microscope of the chromosomes of exceptional females and males. The hypothesis also predicts that exceptional eggs with two X chromosomes fertilized by X-bearing spermatozoa must give individuals with three X chromosomes; such individuals were later identified by Bridges as poorly viable “superfemales.” Exceptional eggs with no Xs, fertilized by Y-bearing spermatozoa, will give zygotes without X chromosomes; such zygotes die in early stages of development.