Prescribing drugs or supplements in pregnancy has to be considered an unusual risk-benefit situation. Life-saving or beneficial drugs for the mother can be harmful for the fetus. There is still uncertainty about the safety of the majority of drugs and supplements. Although pregnancy may favorably be impacted by their use, most of epidemiological and animal studies are severely limited in their power to detect adverse outcomes. This may lead to underprescribing for pregnant women and women of childbearing age. Concerns about drugs and supplements’ prescription in preconception period and in the first trimester, when they can cause birth defects, are mostly quite different from concerns about their use in the second and third trimesters. Communicating the risk-benefit ratio to patients is always a challenge for physicians. A better understanding of the parameters that determine teratogenicity may allow physicians to feel more confident in assessing the risks and benefits associated with prescribing medications in pregnancy.