Progesterone receptors (PR) are useful prognostic indicators of breast cancers likely to respond to anti-estrogen receptor (ER) therapies. However, the role of progesterone, therapeutic progestins, or unliganded or liganded PRin breast cancer development or progression remains controversial. PR are ligand-activated transcription factors that act in concert with intracellular signaling pathways as "sensors" of multiple growth factor inputs to hormonally regulated tissues, such as the breast. The recently defined induction of rapid signaling events upon progestin-binding to PR-B provides a means to ensure that receptors and coregulators are appropriately phosphorylated as part of optimal transcription complexes. PR-activated kinase cascades may provide additional avenues for progestin-regulated gene expression independent of PR nuclear action. Herein, we present an overview ofprogesterone/PR and signaling cross-talk in breast cancer models and discuss the potential significance ofprogestin/PR action in breast cancer biology using examples from both in vitro and in vivo models, as well as limited clinical data. Kinases are emerging as key mediators of PR action. Cross-talk between PR and membrane-initiated signaling events suggests a mechanism for coordinated regulation ofgene subsets by mitogenic stimuli in hormonally responsive normal tissues. Dysregulation of this cross-talk mechanism may contribute to breast cancer biology; further studies are needed to address the potential for targeting PR in addition to ER and selected protein kinases as part of more effective breast cancer therapies.