Keratinocytes, located in the outer part of human skin, are the main epidermal cell type and play an essential role in skins defense against infection. Besides creating a physical barrier between the environment and the internal body, keratinocytes exert powerful immune function in anti-pathogen infection in the skin. At the recognition stage, pattern recognition receptors (PRRs) expressed by keratinocytes sense pathogen-associated molecular patterns (PAMPs) existing in pathogens. Toll like receptors (TLRs) are the most important PRRs in keratinocytes. Other PRRs such as dectin-1 and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are also found to participate in this process. Activated PRRs enhance the secretion of cytokines, chemokines and the production of antimicrobial peptides (AMPs). Proinflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1α, IL-6, IL-1β and IL-18, chemokines (C-X-Cmotif) ligand (CXCL) 1, CXCL2, CCL20, CCL2 and IL-8, AMPs human β-defensin (HBD) 2, HBD3 and LL37 are the main molecules expressed in this procedure. Thymic stromal lymphopoietin (TSLP), IL-36γ, IL-17 family member IL- 17C and anti-inflammatory cytokine IL-10 can also be secreted. Some molecules produced by keratinocytes such as ribonuclease 5 and 7, S100 proteins own antimicrobial properties. Keratinocytes defense responses can be regulated by internal and external factors. This review summarizes recent advances on the innate immune function of keratinocytes against infection, promoting the finding of a new direction for avoiding severe skin infection as well as the potential treatment of keratinocyte-associated inflammatory dermatosis.“,”Keratinocytes, located in the outer part of human skin, are the main epidermal cell type and play an essential role in skins defense against infection. Besides creating a physical barrier between the environment and the internal body, keratinocytes exert powerful immune function in anti-pathogen infection in the skin. At the recognition stage, pattern recognition receptors (PRRs) expressed by keratinocytes sense pathogen-associated molecular patterns (PAMPs) existing in pathogens. Toll like receptors (TLRs) are the most important PRRs in keratinocytes. Other PRRs such as dectin-1 and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are also found to participate in this process. Activated PRRs enhance the secretion of cytokines, chemokines and the production of antimicrobial peptides (AMPs). Proinflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1α, IL-6, IL-1β and IL-18, chemokines (C-X-Cmotif) ligand (CXCL) 1, CXCL2, CCL20, CCL2 and IL-8, AMPs human β-defensin (HBD) 2, HBD3 and LL37 are the main molecules expressed in this procedure. Thymic stromal lymphopoietin (TSLP), IL-36γ, IL-17 family member IL- 17C and anti-inflammatory cytokine IL-10 can also be secreted. Some molecules produced by keratinocytes such as ribonuclease 5 and 7, S100 proteins own antimicrobial properties. Keratinocytes defense responses can be regulated by internal and external factors. This review summarizes recent advances on the innate immune function of keratinocytes against infection, promoting the finding of a new direction for avoiding severe skin infection as well as the potential treatment of keratinocyte-associated inflammatory dermatosis.