Cyclic GMP controls many cellular functions ranging from growth, viability and differentiation, to contractility, secretion and ion transport. The mammalian genome encodes seven transmembrane guanylyl cyclases (GCs), GC-A to GC-G, which mainly modulate submembrane cGMP microdomains. These GCs share a unique topology comprising an extracellular domain, a short transmembrane region, and an intracellular C-terminal catalytic (cGMP synthezising) region. GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure/volume and energy balance. GC-B is activated by C-type natriuretic peptide, stimulating endochondral ossification in autocrine way. GC-C mediates the paracrine effects of guanylins on intestinal ion transport and epithelial turnover. GC-E and GC-F are expressed in photoreceptor cells of the retina and their activation by intracellular Ca2+-regulated proteins is essential for vision. Finally in the rodent system two olfactorial GCs, GC-D and GC-G, are activated by low concentrations of CO2 and by peptidergic (guanylins) and non-peptidergic odorants as well as by coolness, which has implications for social behaviors. In the past years advances in human and mouse genetics as well as the development of sensitive biosensors monitoring the spatiotemporal dynamics of cGMP in living cells have provided novel relevant informations about this receptor family. This increased our understanding of the mechanisms of signal transduction, regulation and (dys)function of the membrane GCs, clarified their relevance for genetic and acquired diseases and, importantly, has revealed novel targets for therapies. The seminar by Michaela Kuhn will illustrate these different features of membrane GCs, with a special focus on GC-A and GC-B, the receptors for natriuretic peptides.