3＇,5＇-Cyclic　adenosine　monophosphate　(cAMP)　is　a　pivotal　second　messenger　that　regulates　numerous　biological　processes　under　physiological　and　pathological　conditions,　including　cancer,　diabetes,　heart　failure,　inflammation,　and　neurological　disorders.　In　the　past,　all　effects　of　cAMP　were　initially　believed　to　be　mediated　by　protein　kinase　A　(PKA)　and　cyclic　nucleotide-regulated　ion　channels.　Since　the　discovery　of　exchange　proteins　directly　activated　by　cyclic　adenosine　5＇-monophosphate　(EPACs)　in　1998,　accumulating　evidence　has　demonstrated　that　the　net　cellular　effects　of　cAMP　are　also　regulated　by　EPAC.　The　pursuit　of　the　biological　functions　of　EPAC　has　benefited　from　the　development　and　applications　of　a　growing　number　of　pharmacological　probes　targeting　EPACs.　In　this　review,　we　seek　to　provide　a　concise　update　on　recent　advances　in　the　development　of　chemical　entities　including　various　membrane-permeable　analogues　of　cAMP　and　newly　discovered　EPAC-specific　ligands　from　high　throughput　assays　and　hit-to-lead　optimizations.