3',5'-Cyclic guanosine monophosphate (cGMP) is a ubiquitous second messenger, which critically regulates cardiac pump function and protects from the development of cardiac hypertrophy by acting in various subcellular microdomains. Although clinical studies testing the potential of cGMP elevating drugs in patients suffering from cardiac disease showed promising results, deeper insight into the local actions of these drugs at the subcellular level are indispensable to inspire novel therapeutic strategies. Detailed information on the spatio-temporal dynamics of cGMP production and degradation can be provided by the use of fluorescent biosensors that are capable of monitoring this second messenger at different locations inside the cell with high temporal and spatial resolution. In this review, we will summarize how these emerging new tools have improved our understanding of cardiac cGMP signaling in health and disease, and attempt to anticipate future challenges in the field.