These premises together with our original finding that the NO pathway represents a “primum movens” of a transcriptional program promoting the acquisition of an aggressive phenotype in PCa cells, and that the nuclear translocation of eNOS significantly affects chromatin remodeling of a specific subset of PCa prognostic genes [17], has prompted us to investigate the full potential of this key signaling molecule as master gene in the progression of prostate cancer. The gene discussed is NOS3; the disease is prostate cancer.