Immunologists view innate immunity as evolution's ancient host response to infectious agents. Unlike vertebrates, in which antibodies and T-cell subsets rely on somatic mutations, molecular participants of innate immunity are encoded in the genome. Despite its heritage, many of innate immunity's sentinel molecules, intracellular transcriptional controls, and effector molecules participate in the pathogenesis of numerous complex human diseases. Toll-like receptors (TLRs), an important starting point, contact the environment and provide specific sensing for an important component of innate immunity. TLRs, found on macrophages, dendritic cells, and endothelial cells, recognize specific microbial molecular patterns. Beginning with these sentinel molecules, the process leads through intracytoplasmic mediators of transcription control and culminates with an array of host immune responses. Effector molecules include cytokines and the complement system. Polymorphisms within TLR genes might contribute to the pathogenesis of complex diseases. Disease associations linked to single nucleotide polymorphisms are in the early stage of experimental discovery; important clinical insights are emerging. Along these lines, studies of asthma provide an excellent example of how ancient ligand-receptor interactions and TLR polymorphisms provide new understanding of a common disease. New knowledge could facilitate the development of novel therapies.