Therapeutic resistance has been and remains to be the major challenge in developing successful treatments for different cancers and therefore, understanding the underlying mechanisms in the development of therapeutic resistance is crucial in combating cancers. Multiple mechanisms underlie the development of therapeutic resistance, and the signaling pathways involved in cancer stem cell repopulation, enhanced epithelial-mesenchymal transition (EMT), inflammatory infiltration, and immunosuppression play pivotal roles in this process. Accumulating evidence indicates that the COX2/PGE2/EP axis plays crucial roles not only in tumor development including initiation and progression but also in the development of therapeutic resistance. In this review, we will first dissect the relationship between the COX2/PGE2/EP axis and therapeutic resistance by focusing on the roles of the COX2/PGE2/EP axis in cancer stem cell repopulation, EMT, and anti-cancer immunity. Then, we will summarize the currently available compounds/drugs targeting each component of this axis as well as some of the underlying mechanisms. We hope that better understanding the underlying mechanisms of the functional compounds will be helpful in seeking additive and/or synergistic effects against therapeutic resistance without or with minimal adverse consequence.