Recent advances in our understanding of the molecular basis of mammalian host immune responses to microbial invasion suggest that the first line of defense against microbes is the recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs). Phosphoinositide 3-kinase (PI3K) is thought to participate in the TLR signaling pathway. The activation of PI3K is commonly observed after stimulation with various TLR ligands. The resultant activation of a serine-threonine protein kinase Akt leads to the phosphorylation of glycogen synthase kinase (GSK)-3beta, which is active in resting cells but is inactivated by phosphorylation. GSK-3beta has been linked to the regulation of a multitude of transcription factors, including NF-kappaB, AP-1, NF-AT, and CREB either negatively or positively. Thus, the altered activity of GSK-3beta causes diverse effects on cytokine expression. Generally, activation of PI3K results in the inhibition of proinflammatory events such as expression of IL-12 and TNF-alpha. Thus, PI3K is a negative regulator of TLR signaling. Among the members of the Class I PI3K family, p85/p110beta appears to be the subtype activated on TLR ligation, but the molecular basis for this specificity has yet to be elucidated.