Adverse effects in infants due to the ingestion of drugs and other xenobiotics remain an area of concern. A key parameter in assessing infant exposure via breast milk, the milk to plasma concentration ratio (M/P), has not been determined in vivo in humans for most drugs. There are various methods for predicting M/P, which involve in vitro experiments in mammary cell monolayers, assessment of drug binding to plasma and milk protein and lipid, in vivo experiments in animals, and regression models based on a compound's physicochemical characteristics. This article reviews these approaches in terms of their utility, advantages and disadvantages. Some combination of these methods is necessary for reasonably accurate prediction of M/P in humans.