Cyclic nucleotide signal transduction pathways are an emerging research field in kidney disease. Activated cell surface receptors transduce their signals via intracellular second messengers such as cyclic AMP and cyclic GMP (cGMP). There is increasing evidence that regulation of the cGMP-cGMP-dependent protein kinase1-phosphodiesterase (cGMP-cGK1-PDE) signaling pathway may be renoprotective. Selective PDE5 inhibitors have shown potential in treating kidney fibrosis in patients with chronic kidney disease, via their downstream signaling, and these inhibitors also have known activity as anti-thrombotic and anti-cancer agents. This review gives an outline of the cGMP-cGK1-PDE signaling pathways and details the downstream signaling and regulatory functions that are modulated by cGK1 and PDE inhibitors with regards to anti-fibrotic, anti-thrombotic and anti-tumor activity. Current evidence that supports the renoprotective effects of regulating cGMP-cGK1-PDE signaling is also summarized. Finally, the effects of icariin, a natural plant extract with PDE5 inhibitory function, are discussed. We conclude that regulation of cGMP-cGK1-PDE signaling might provide novel, therapeutic strategies for the worsening global public health problem of chronic kidney disease.