Progesterone is an essential regulator of normal female reproductive function, yet recent studies on the use of progestins in hormone replacement therapy have clearly implicated progestins in breast cancer development, a disease initiated early in life at a time of frequent exposure to cycling ovarian hormones. The effects of progesterone are mediated by two distinct nuclear receptor proteins, PRA and PRB. In normal breast PRA and PRB are co-expressed at similar levels in luminal epithelial cells, suggesting that both proteins are required to mediate physiologically relevant progesterone signalling. However, early in breast carcinogenesis PRA:PRB expression is disrupted, resulting in frequent predominance of one isoform. Unbalanced expression of PRA and PRB results in altered hormonal response and aberrant targeting of genes that are not normally progestin-regulated, principally those involved in morphological changes and disruptions of the actin cytoskeleton, and in migration. Movement of PR into discrete nuclear domains, or foci, is a critical step in normal PR transcriptional activity that appears to be aberrant in cancers and likely related to alterations in nuclear morphology, gene expression and cell function associated with tumour cells. Given that exogenous progestins are consumed by millions of women worldwide in the form of hormone replacement therapy and oral contraceptives, it is vital to better understand the mechanisms of progesterone action in the breast.