Nontypeable Haemophilus influenzae (NTHi) is an important human pathogen causing respiratory infectious diseases. Although tremendous effort has been put towards identifying the surface molecules of NTHi for vaccine development, it is actually quite recent that we have begun to appreciate the intricate host epithelial signaling networks activated by NTHi. From what has been reported, it is evident that NTHi activates multiple signaling pathways in host epithelial cells that, in turn, inadvertently contribute to the pathogenesis, such as mucus overproduction mainly results from up-regulation of mucin. Over the past decades, substantial studies revealed that mucin, a primary innate defensive response for mammalian airways, plays an important role in the pathogenesis of respiratory infectious diseases. Among multiple signaling pathways activated in NTHi infection, p38 MAPK leads to up-regulation of MUC5AC mucin gene expression, whereas NF-kB mediates NTHi-induced MUC2 mucin gene up-regulation. Moreover, in contrast to its positive involvement in NTHi-induced MUC2 transcription, TGF-β-Smad signaling pathway, however, serves as a negative regulator for NTHi-induced MUC5AC transcription. Finally, under in vivo diseased situation, multiple stimulators, such as S. pneumoniae or EGF, synergized with NTHi to potently up-regulate MUC5AC mucin transcription. Understanding the signaling mechanisms underlying up-regulation of mucin may bring new insights into the molecular pathogenesis of NTHi infections and open up novel therapeutic targets for these diseases.