Toll-like receptor 2 (TLR2) is a member of the TLR family, which plays a central role in the innate immune response to a wide variety of microorganisms. Animal studies have shown that TLR2-knockout mice are more susceptible to septicemia due to Staphylococcus aureus and Listeria monocytogenes, meningitis due to Streptococcus pneumoniae, and infection with Mycobacterium tuberculosis, suggesting that functional TLR2 polymorphisms may impair host response to a certain spectrum of microbial pathogens. In humans, 2 polymorphisms in the exon part of TLR2, which attenuate receptor signaling, enhance the risk of acute severe infections, tuberculosis, and leprosy. Because gram-positive bacteria have became the first cause of severe infections, including septic shock, knowledge of the role that alteration or lack of TLR2 function plays in the pathogenesis of infectious diseases could contribute to the design of new therapeutic strategies, including prevention, pharmacological intervention, and vaccine development.