The ever-increasing number of chemicals to which humans are exposed, together with a recognition that some of them are potentially harmful to the male reproductive system, have driven the development of male reproductive toxicology. This was given a boost in 1992 when a 50% decline in sperm counts over the preceding 50 years was reported (Carlsen et al., Br Med J 305:609–613, 1992), stimulating a huge amount of research into adverse effects on the male reproductive system. Somewhat contentious at the time, the claim has nevertheless been supported by similar, subsequent research (Levine et al., Hum Reprod Update 23:646–659, 2017) that was specifically designed to avoid the problems with the earlier study. Even so, no clear cause for the decline has yet been established. In general, adverse effects on the reproductive system have been found experimentally with a wide range of chemicals but relatively rarely under conditions comparable to human exposure. Population-wide monitoring bears this out with only very small effects on reproductive parameters detectable. The nematocide dibromochloropropane is the classic example of an industrial compound that affects the male reproductive system but there is little evidence that many other toxic agents (e.g. metals, complex organochlorine compounds, alcohol, electromagnetic radiation, heat) have comparable effects at normal exposure and adult susceptibility levels. Certain other agents, particularly smoking and ionising radiation, only show limited heritable effects under certain (usually chronic) exposures. The principal risk to sperm production is from anti-cancer therapies, although the available (albeit limited) evidence indicates no heritable effects, perhaps because the exposures are high dose and acute or sub-chronic. Nevertheless, there is considerable concern that unknown factors in the environment, possibly with endocrine disrupting characteristics, are capable of inducing a range of effects sometimes now grouped together as testicular dysgenesis syndrome. Although there is abundant experimental and environmental evidence that a wide range of specific toxins, especially endocrine-disrupting compounds, can induce such effects, epidemiological evidence in humans is mixed (Rodprasert et al., Front Endocrinol 12:706532, 2021). Consequently, the current legislative framework for regulating exposures that could harm the male reproductive system, has not substantively altered in recent years: with the one exception that guidelines have been introduced for the testing of endocrine disruptors. This is also because the roots of male reproductive toxicity in humans are still only poorly understood. Exciting developments over the last decade however, may be pointing the way towards a better understanding of the mechanisms involved.