Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PG), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiological functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biological actions by binding to their respective receptors namely IP and EP1-4. They belong to the family of G protein–coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals and genome wide association studies (GWAS) regarding the roles of IP and EP1-4 receptor in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary and musculoskeletal systems. In particular, we highlight similarities and differences between humans and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biological system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the science, animal models and human studies.