Progesterone exhibits diverse biological activities, inducing proliferation of the mammary gland epithelium, but it opposes the mitogenic activity of estrogen in the uterus. These tissue-selective activities of progesterone are mediated by the progesterone receptor (PR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Several clinically useful PR antagonists that block progesterone activity have been described, yet some of these compounds exhibit tissue-selective partial agonist activity, leading them to be termed selective progesterone receptor modulators (SPRMs). This partial agonist activity is mediated primarily through the N-domain of the B isoform of PR, although the mechanism has not yet been defined. In this review, we discuss mechanisms by which PR activates transcription and ways in which antagonists oppose progesterone activity. We discuss mechanisms by which the N-domain mediates tissue specific partial agonist activity of SPRMs, as well as receptor interacting coregulatory proteins that influence this activity of the N-domain. We also describe newly developed SPRMs that mediate subsets of agonist and/or antagonist activities, and discuss the clinical potential of these compounds.