Loss of function of the kinase IRAK4 or the adaptor MyD88 in humans interrupts a pathway critical for pathogen sensing and ignition of inflammation. However, patients with loss-of-function mutations in the genes encoding these factors are, unexpectedly, susceptible to only a limited range of pathogens. We employed a systems approach to investigate transcriptome responses following in vitro exposure of patients' blood to agonists of Toll-like receptors (TLRs) and receptors for interleukin 1 (IL-1Rs) and to whole pathogens. Responses to purified agonists were globally abolished, but variable residual responses were present following exposure to whole pathogens. Further delineation of the latter responses identified a narrow repertoire of transcriptional programs affected by loss of MyD88 function or IRAK4 function. Our work introduces the use of a systems approach for the global assessment of innate immune responses and the characterization of human primary immunodeficiencies.