The heterodimeric haemoprotein soluble guanylate cyclase (sGC) acts as the intracellular receptor for nitric oxide (NO), thereby mediating most effects of NO in its function as signalling molecule. Organic nitrates (e.g. glycerol trinitrate, isosorbide trinitrate) are bioconverted in vivo to form NO. The work describes the identification and characterization of two distinct classes of non NO-based sGC activating compounds: haem-dependent sGC stimulators and haem-independent sGC activators. These novel sGC activators are important both as pharmacological tools and in the development of new therapeutics. These compounds have revealed previously unknown regulatory sites on the enzyme which may be important physiologically, representing target sites for endogenous molecules modulating sGC activity. The therapeutic benefits of these compounds are clear in the cardiovascular system, having a profile of activity similar to organic nitrates, but devoid of the problem of tolerance. Moreover, these compounds have distinct anti-platelet activity, which organic nitrates do not, which is theoretically beneficial for diseases such as angina and heart failure. These reagents should therefore offer significant advantage over current therapy.