Endometriosis is characterised by the presence of endometrium-like tissue on the pelvis and other organs. Progesterone resistance due to suppressed progesterone receptor (PGR) expression and action is a general feature of endometriosis and is a cause of endometriosis-associated chronic pelvic pain, infertility, inflammatory disorders, and cancer. It appears that progesterone receptor polymorphisms may not be associated with the susceptibility to endometriosis. On the other hand, PGR expression and activity in target cells is significantly dysregulated in both eutopic and ectopic tissues compared with control endometrium. However, the underlying epigenetic mechanisms for PGR suppression in the eutopic tissue are different from ectopic tissue. The aim of this paper was to present an overview of different aspects of progesterone resistance and its application in endometriosis. Finally, this article also presents a few important, unmet questions related to the failure of progesterone treatment in alleviating clinical conditions in endometriosis.