The Toll-like receptor (TLR) family regulates both innate and adaptive immune responses. Given its broad effect on immunity, the function of TLRs in various human diseases has been investigated largely by comparing the incidence of disease among persons with different polymorphisms in the genes that participate in TLR signaling. These studies demonstrate that TLR function affects several diseases, including sepsis, immunodeficiencies, atherosclerosis, and asthma. These findings have resulted in new opportunities to study the pathogenesis of disease, identify subpopulations at greater risk of disease, and, potentially, identify novel therapeutic approaches.