In the breast, data from numerous laboratories suggest that cross-talk exists between PR and growth factor and cytokine signaling pathways at multiple levels (Fig. 4). At the cell surface (level 1), progestins up-regulate growth factor and cytokine receptors. We have expanded this observation by examining the effects of progestins in the cytoplasm (level 2) where progestins regulate several intracellular effectors by increasing the levels and altering the subcellular compartmentalization of Stat5, increasing the association of Stat5 with phosphotyrosine-containing proteins and tyrosine phosphorylation of JAK2, Cbl, and Shc, and potentiating EGF-stimulated p42/p44 MAPKs, p38 MAP kinase, and JNK activities. Together, these events lead to sensitization of downstream signaling pathways to the actions of locally acting secondary factors. Finally, inside the nucleus (level 3), agonist-occupied PR synergize with nuclear transcription factors that are growth-factor regulated, to control the activity of key genes involved in breast cell fate (Figs. 1 and 4). We speculate that after progesterone treatment, orchestrated combinations of steroid hormones and growth factors or cytokines can fine tune the timing and degree of expression of a subset of genes that determine whether progestin-primed cells undergo proliferation, differentiation, or programmed cell death. The paradoxical effects of progesterone have presented a longstanding conundrum to the scientist and clinician. Why are physiological levels of progesterone proliferative in the breast but antiproliferative and protective in the uterus? If progesterone is proliferative in the breast, why is high-dose progestin therapy successful in treating breast cancer? Our intent here has been to open a dialogue addressing these questions. Our data and that of others are beginning to show that one cannot approach the question of progestin actions in isolation. Other important regulatory proteins, whose expression may vary in tissue-specific ways, work in concert with progesterone to decide cell fate. The timing and dose of progesterone may also influence the biological response. Since progestins are widely used in oral contraception, in hormone replacement therapy, and in cancer treatments, it is becoming critically important that the subtleties of their mechanisms of action be clearly understood.