The G-protein coupled receptors EP2 and EP4 both transduce the signal of the lipid messenger Prostaglandin E2 (PGE2). Changes in the cell response to PGE2 can have important effects on immunity and development of diseases, however, a thorough understanding of the EP2-EP4 receptors' signaling pathways is lacking. Experimental data show that receptor activity (indicated by cAMP expression) has a different kinetics depending on which receptor is triggered by PGE2 and that crosstalk exists between EP2 and EP4. To better understand the underlying mechanisms and be able to predict cell responses to PGE2, we develop novel mathematical models for the cAMP signaling pathways of EP2 and EP4 and their crosstalk. Ligand binding dynamics plays a crucial role for both, the single receptor activity and their crosstalk. The mathematical models can predict the qualitative cAMP levels observed experimentally and provide possible explanations for the differences and commonalities in the signaling behavior of EP2 and EP4. As inhibition of PGE2 signaling is gaining increasing attention in tumor immunology, these mathematical models could contribute to design effective anti-tumor therapies targeting EP2 and EP4.