Current international classification systems for chemical mutagens are hazard-based rather than aimed at assessing risks quantitatively. In the past, germ-cell tests have been mainly performed with a limited number of somatic cell mutagens, and rarely under conditions aimed at comparing gender-specific differences in susceptibility to mutagen exposures. There are profound differences in the genetic constitution, and in hormonal, structural, and functional aspects of differentiation and control of gametogenesis between the sexes. A critical review of the literature suggests that these differences may have a profound impact on the relative susceptibility, stage of highest sensitivity and the relative risk for the genesis of gene mutation, as well as structural and numerical chromosomal aberrations in male and female germ cells. Transmission of germ-cell mutations to the offspring may also encounter gender-specific influences. Gender differences in susceptibility to chemically derived alterations in imprinting patterns may pose a threat for the health of the offspring and may also be transmitted to future generations. Recent reports on different genetic effects from high acute and from chronic low-dose exposures challenge the validity of conclusions drawn from standard methods of mutagenicity testing. In conclusion, research is urgently needed to identify genetic hazards for a larger range of chemical compounds, including those suspected to disturb proper chromosome segregation. Alterations in epigenetic programming and their health consequences will have to be investigated. More attention should be paid to gender-specific genetic effects. Finally, the database for germ-cell mutagens should be enlarged using molecular methodologies, and genetic epidemiology studies should be performed with these techniques to verify human genetic risk.