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Clinical genetics has typically dealt with rare disorders caused by single genes that produce a disease phenotype, and this is the arena in which clinical genetics has been overwhelmingly successful in identifying the genetic etiology of disease. Despite these successes, medical genetics has yet to have a major impact on the many of the common multi-factorial diseases that fill up hospital beds. Clinical genetic approaches to understanding complex diseases and environmental interactions continue to hold significant promise. The study of genetic susceptibility to infectious diseases is an emerging area of research that combines the strengths of molecular genetics, with the public health impact of improving treatments for common infectious diseases. Such investigations will likely bear fruit not only in terms of understanding basic immunology, but may also lead to novel targets for the treatment and prevention of infectious diseases, and may lead to answers to fundamental questions like ‘why do some people get sick while others do not’? Picard and colleagues studied three unrelated individuals who suffered from recurrent lifethreatening pyogenic infections during the first 5 years of life, caused predominantly by Staphylococcus aureus and Streptococcus pneumoniae. These infections included arthritis, cellulites, impetigo, liver abscesses, osteomyelitis, septicemia, sinusitis, otitis media, pneumonia and meningitis. All three children had minimal or absent febrile and inflammatory responses and developed transient neutropenia during these infections. The children showed otherwise normal growth and development, and by the ages of 6–11 years had ceased to suffer from recurrent infections. Primary immunodeficiencies were excluded as a cause of the recurrent infections in all three children, and antibodies to S. pneumoniae were found to be present. One of the individuals had been previously shown to have an impaired immune response to lipopolysaccharide (LPS). Because LPS is recognized primarily by Toll-like receptor 4 (TLR4), this observation raised the possibility that these children suffered from a defect in the common Toll-IL-1 receptor (TIR) signaling pathway (Fig. 1). Both the toll-like receptors and interleukin-1 (IL-1) receptor superfamily are characterized by the presence of an intracytoplasmic Toll-IL-1 receptor domain. These receptors recognizeavarietyofpathogen-associatedmolecular patterns, and serve to activate the innate immune system in response to various microbial signals. Upon ligand binding, the TIR domain recruits the cytoplasmic adapter proteins, MyD88 and TIRAP/Mal, which subsequently activate members of the interleukin-1 receptorassociated kinase (IRAK) complex. Both IRAK1 and IRAK-4 are active kinases, and the phosphorylation of these molecules leads to dissociation from the IRAK complex and association with tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6). TRAF-6 mediates the downstream activation of at least two pathways: nuclear factor kB and the mitogen-activated protein kinase (MAPK). To address the hypothesis that these children had a defect in this important and common pathway of innate immunity, blood cells from these patients were isolated and tested for response to various bacterial stimuli and inflammatory ligands. Blood cells from all three patients were found to have impaired response to LPS, as detected by TNF-a production. Further tests were performed on additional cells from two of the patients. Blood cells were found to be defective in responding to IL-12, and IL-1/IL-8 in combination. However, these cells responded normally to TNF-a stimulation by producing Clin Genet 2003: 64: 104–110 Copyright # Blackwell Munksgaard 2003 Printed inDenmark. All rights reserved CLINICALGENETICS 0009-9163