Guanylyl cyclases (GCs) are enzymes that convert guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophosphate (cGMP). The second messenger cGMP participates in signaling by (1) stimulating the activity of kinases that belong to the protein kinase G family, (2) altering the conductance of cGMP-gated ion channels and (3) changing the activity of cGMP-regulated phosphodiesterases. In contrast to adenylyl cyclases which exist as membrane-bound molecules, guanylyl cyclases (GC) occur in both membrane-bound and cytosolic forms. The particulate GC (pGC) isoforms serve as receptors for natriuretic peptides, while soluble GC (sGC) is the "receptor" for nitric oxide (NO). In addition to the difference in ligands and subcellular organization, the two forms of GC also differ in that pGC exists in homodimeric form, while typically sGC occurs as a heterodimer. Herein, we will review the literature on sGC subunit structure and discuss the regulation of the enzyme at the transcriptional and post-translational level.