The cAMP/PKA pathway is one of the most important signalling pathways widely distributed in most eukaryotic cells. The activation of the canonical cAMP/PKA pathway depends on transmembrane adenylyl cyclase (tmAC). Recently, soluble adenylyl cyclase (sAC), which is activated by HCO3− or Ca2+, emerges to provide an alternative way to activate cAMP/PKA pathway with the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP‐activated Cl−/HCO3−‐conducting anion channel, as a key player. This review summarizes new progress in the investigation of the CFTR/HCO3−‐dependent sAC signalling and its essential role in various reproductive processes, particularly in ovarian functions. We present the evidence for a CFTR/HCO3−‐dependent nuclear sAC signalling cascade that amplifies the FSH‐stimulated cAMP/PKA pathway, traditionally thought to involve tmAC, in granulosa for the regulation of oestrogen production and granulosa cell proliferation. The implication of the CFTR/HCO3−/sAC pathway in amplifying other receptor‐activated cAMP/PKA signalling in a wide variety of cell types and pathophysiological processes, including aging, is also discussed.