Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disorder associated with polycystic liver disease (PLD) and other extrarenal manifestations, the most common monogenic cause of end-stage kidney disease, and a major burden for public health. Many studies have shown that alterations in G-protein and cAMP signaling play a central role in its pathogenesis. As for many other diseases (35% of all approved drugs target G-protein coupled receptors (GPCRs) or proteins functioning upstream or downstream from GPCRs), treatments targeting GPCR have shown effectiveness in slowing the rate of progression of ADPKD. Tolvaptan, a vasopressin V2 receptor antagonist is the first drug approved by regulatory agencies to treat rapidly progressive ADPKD. Long-acting somatostatin analogs have also been effective in slowing the rates of growth of polycystic kidneys and liver. Although no treatment has so far been able to prevent the development or stop the progression of the disease, these encouraging advances point to G-protein and cAMP signaling as a promising avenue of investigation that may lead to more effective and safe treatments. This will require a better understanding of the relevant GPCRs, G-proteins, cAMP effectors, and of the enzymes and A-kinase anchoring proteins controlling the compartmentalization of cAMP signaling. The purpose of this review is to provide an overview of general GPCR signaling; the function of polycystin-1 (PC1) as a putative atypical adhesion GPCR (aGPCR); the roles of PC1, polycystin-2 (PC2) and the PC1-PC2 complex in the regulation of calcium and cAMP signaling; the cross-talk of calcium and cAMP signaling in PKD; and GPCRs, adenylyl cyclases, cyclic nucleotide phosphodiesterases, and protein kinase A as therapeutic targets in ADPKD.