Hydrogen sulfide, nitric oxide, and carbon monoxide are endogenously produced gases that regulate various signaling pathways. The role of these transmitters is complex as constitutive production of these molecules may have anti-inflammatory, anti-microbial, and/or vasodilatory effects whereas induced production or formation of secondary metabolites may lead to cellular death. Given this fine line between friend and foe, therapeutic attenuation of these molecules’ production has involved both inhibition of endogenous formation and therapeutic supplementation. All three gases have been implicated as regulators of critical aspects of neonatal physiology, and in turn, comorbidities including necrotizing enterocolitis, hypoxic ischemic encephalopathy, and pulmonary hypertension. In this review, we present current perspectives on these associations, highlight areas where insights remain sparse, and identify areas for potential for future investigations.