Emerging evidence reveals that pattern-recognition receptors (PRRs), Toll-like receptors (TLRs), and nucleotide-binding oligomerization domain proteins (NODs) mediate both infection-induced and sterile inflammation by recognizing pathogen-associated molecular patterns and endogenous molecules, respectively. PRR-mediated chronic inflammation is a determinant for the development and progression of chronic diseases including cancer, atherosclerosis, and insulin resistance. Recent studies demonstrated that certain phytochemicals inhibit PRR-mediated pro-inflammation. Curcumin, helenalin, and cinnamaldehyde with α, β-unsaturated carbonyl groups, or sulforaphane with an isothiocyanate group, inhibit TLR4 activation by interfering with cysteine residue-mediated receptor dimerization, while resveratrol, with no unsaturated carbonyl group, did not. Similarly, curcumin, parthenolide, and helenalin, but not resveratrol and (-)-epigallocatechin-3-gallate (EGCG), also inhibit NOD2 activation by interfering with NOD2 dimerization. In contrast, resveratrol, EGCG, luteolin, and structural analogs of luteolin specifically inhibit TLR3 and TLR4 signaling by targeting TANK binding kinase 1 (TBK1) and receptor interacting protein 1 (RIP1) in Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) complex. Together, these results suggest that PRRs and downstream signaling components are molecular targets for dietary strategies to reduce PRR-mediated chronic inflammation and consequent risks of chronic diseases.