Rapid progress has recently been encountered in pharmacologically treating the unborn baby. This unique area of drug therapy raises new methodological and ethical questions. This article is a systematic review of known modalities of fetal pharmacotherapy, and aims to highlight essential principles, difficulties and controversies in fetal pharmacotherapy. Unique pharmacokinetic features of pregnancy, the placenta and the fetus govern maternal-to-fetal drug transfer. Ethically, it is important that the mother and family are appropriately informed about the evidence in favour of specific fetal therapy, its risks and alternatives. Antenatal use of corticosteroids for lung maturation is an example of adequate methodology, leading to clear results. In contrast, the initial hopes in antenatal use of phenobarbital were based on less than optimal methodology. Folic acid for the prevention of neural tube defects is the first instance of fetal therapy that has led to the prevention of a major malformation. Serious infections, such as HIV, Group B streptococcus and toxoplasmosis highlight the need for controlled, randomised studies to prevent fetal infection. With scores of new modalities of fetal therapy likely to be introduced in the next few years, it will be important to adhere to the best possible methodology and execution, in order to address optimally the needs of the fetus.