Common comorbid diseases such as obesity, diabetes mellitus and hypertension are the main causes of death and disability around the globe. Available medications of such complex diseases are symptomatic, do not target the underlying cause, and lack precision. A core reason for this medical knowledge gap is that these multifaceted disorders are often described by symptoms in certain organ and not by a molecular causal mechanism. Systems medicine, however, shows that these comorbidities are closely linked and clustered within the human disease network (also known as the diseasome). Therefore, such clusters likely share common causal pathophysiological mechanisms, and targeting these pathomechanisms would be superior to symptom-based therapeutics. These mechanisms are not a single molecular target, yet small signaling networks or modules of multiple targets. Thus, targeting multiple targets in a single module by mechanistically related drugs i.e., network pharmacology is superior to single target strategies. In this mini review, we discuss one example of causal signaling modules consisting of targets related to reactive oxygen species (ROS) and nitric oxide (NO) signaling.