Methotrexate, an anti-folate, and misoprostol, a prostaglandin E1-analog, are both used for disease treatment and prevention, and for ectopic or intrauterine pregnancy termination, respectively. Methotrexate is a potent teratogen after early pregnancy higher-dose administration. Methotrexate-embryopathy includes facial dysmorphism, craniosynostosis, heart defects and limb abnormalities, often accompanied by growth deficiency. Misoprostol, however, is associated with a smaller risk to the embryo, mainly for limb defects and for Mӧbius sequence. In this narrative review, the literature on the effect of early pregnancy exposure to these drugs on the embryo is discussed with critical evaluation of the evidence from the first signal to current knowledge, regarding the phenotype, dose, timing in pregnancy, biological plausibility, consistency between studies, and risk estimate. Some open questions and legal, social, and political aspects of their use are addressed. Despite the risk to the embryo, these medications have an important role in women's health.