Lactation is a dynamic process that has evolved to produce a complex biological fluid that provides nutritive and non-nutritive factors to the nursing offspring. It has long been assumed that once lactation is successfully initiated, the primary factor regulating milk production is infant demand. Thus most interventions have focused on improving breastfeeding education and early lactation support. However, in addition to infant demand, increasing evidence from studies conducted in experimental animal models, production animals and breastfeeding women suggests that a diverse array of maternal factors may also affect milk production and composition. In this review, we provide an overview of our current understanding of the role of maternal genetics and modifiable factors, such as diet and environmental exposures, on reproductive endocrinology, lactation physiology and the ability to successfully produce milk. In order to identify factors that may affect lactation in women, we highlight some information gleaned from studies in experimental animal models and production animals. Finally, we highlight the gaps in current knowledge and provide commentary on future research opportunities aimed at improving lactation outcomes in breastfeeding women to improve the health of mothers and their infants.