Hydrogen sulfide (HS) is the "third gasotransmitter" recognized alongside nitric oxide (NO) and carbon monoxide (CO). HS exhibits an array of biological effects in mammalian cells as revealed by studies showing important roles in the cardiovascular system, in cell signalling processes, post-translational modifications and in the immune system. Regarding the latter, using pharmacological and genetic approaches scientists have shown this molecule to have both pro- and anti-inflammatory effects in mammalian systems. The anti-inflammatory effects of HS appeared to be due to its inhibitory action on the nuclear factor kappa beta signalling pathway; NF-kB representing a transcription factor involved in the regulation pro-inflammatory mediators like nitric oxide, prostaglandins, and cytokines. In contrast, results from several animal model describe a more complicated picture and report on pro-inflammatory effects linked to exposure to this molecule; linked to dosage used and point of administration of this molecule. Overall, roles for HS in several inflammatory diseases spanning arthritis, atherosclerosis, sepsis, and asthma have been described by researchers. In light this work fascinating research, this chapter will cover HS biology and its many roles in the immune system.