Structural heterozygosities of the karyotype have detrimental effects on the meiotic process, resulting very often in impairment of fertility in the carriers. Both male and female germ cell development are affected by chromosomal variability although spermatogenesis seems particularly prone to be affected, probably because of the intrinsic characteristics of the male germ cell cytodifferentiation process (i.e. the histological architecture of the seminiferous epithelium). However, euploid and aneuploid sperm do not seem to differ in the molecular organization of the genome they carry, thus explaining the almost regular capacity to accomplish the first zygotic developmental stages by the aneuploid sperm (aneuploid both for gametogenic genes and for entire chromosomal arms). A survey of the molecular and morphological data available on germ cell development in conditions of chromosomal rearrangement leads to the conclusion that the current hypotheses accounting for this phenomenon can only partly explain it. A working hypothesis is proposed which considers the three-dimensional changes (produced by structural heterozygosity) in the spatial order of chromosomes within the nucleus as the primary cause potentially able to trigger distorted functioning of the germ cells.