There is a growing interest in “medical gases” for their role in infection. Hydrogen sulfide (H2S) is a physiological gaseous mediator that has been recognized as an important signalling molecule to regulate infections. The role of H2S in different infections such as viruses (paramyxoviruses), bacteria (Mycobacterium tuberculosis), mycoplasma (Mycoplasma fermentans) and fungi (Aspergillus niger) as well as in conditions like sepsis and malaria and in antibiotic resistance is being actively investigated because of its therapeutic potential. As we do not have definitive therapeutic agents such as antimicrobials or vaccines against many pathogenic agents, the immuno-regulatory and microbial properties of H2S make it an ideal candidate for the treatment of infectious diseases. Therefore, understanding the mechanisms underlying H2S-mediated regulation of different infectious diseases would help in developing H2S-based drugs as therapeutic molecules. A description of recent understanding of H2S role in different infections is presented in this chapter.