The results of many recent experimental and clinical studies support the hypothesis that progesterone administered vaginally is distributed selectively to the uterus where tissue concentrations and effects exceed expectations. This phenomenon has multiple clinical implications in several fields of gynaecological endocrinology, notably in assisted reproductive treatments and new forms of hormone replacement therapy. Yet, the actual mechanisms by which vaginal administration of progesterone can induce higher concentrations in the uterus, despite low concentrations in the systemic circulation, remain obscure and most puzzling to many gynaecologists. This review aims to muster ideas and propose different mechanisms to explain the observed phenomenon. In particular, we will summarize data that support the various putative modes of transport including, direct diffusion through tissue, intracervical aspiration, absorption into the venous or lymphatic circulatory systems and countercurrent vascular exchange with diffusion from utero-vaginal veins/lymph vessels to arteries. All these mechanisms may concur to various extents to the uterine specificity of vaginal progesterone.