Soluble guanylate cyclase (sGC) is the intracellular receptor of messenger nitric oxide (NO). The activation of sGC results in the conversion of guanosine triphosphate (GTP) to the secondary messenger cyclic guanosine monophosphate (cGMP). cGMP modulates a series of cascades downstream through activating a variety of effectors, such as phosphodiesterase (PDE), protein kinase G (PKG), cyclic nucleotide gated ion channels (CNG). The NO-sGC-cGMP pathway play significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. Riociguat, as a sGC stimulator, has been approved for the treatment of pulmonary arterial hypertension (PAH), but enthusiasm on discovery of sGC modulators continues for their potential new applications. Notably, through activating the pathway, sGC stimulators and activators are potential therapies for the treatment of diverse diseases, such as PAH, heart failure (HF), diabetic nephropathy (DN) and systemic sclerosis (SS) as well as other diseases including sickle cell disease (SCD) and central nervous system (CNS) disease. Here, we review the preclinical and clinical studies of sGC stimulators and activators covering different diseases in recent five years and prospect the development of sGC modulators in the near future.