In vitro nine of 10 known human Toll‐like receptors (TLRs) are engaged by well‐defined chemical agonists that mimic microbial compounds, raising the possibility that human TLRs play a critical role in protective immunity in vivo. We thus review here the recently described human primary immunodeficiencies caused by germline mutations in genes encoding molecules involved in cell signaling downstream from TLRs. Subjects with anhidrotic ectodermal dysplasia with immunodeficiency (EDA‐ID) carry either X‐linked recessive hypomorphic mutations in NEMO or autosomal dominant hypermorphic mutations in IKBA. Their cells show a broad defect in nuclear factor‐κB (NF‐κB) activation, with an impaired, but not abolished response to a large variety of stimuli including TLR agonists. EDA‐ID patients show developmental anomalies of skin appendages and a broad spectrum of infectious diseases. Patients with autosomal recessive amorphic mutations in IRAK4 present a purely immunological syndrome and more restricted defects, with specific impairment of the Toll and interleukin‐1 receptor (TIR)–interleukin‐1 receptor‐associated kinase (IRAK) signaling pathway. In these subjects, the NF‐κB‐ and mitogen‐activated protein kinase‐mediated induction of inflammatory cytokines in response to TIR agonists is impaired. The patients present a narrow range of pyogenic bacterial infections that become increasingly rare with age. Altogether, these data suggest that human TLRs play a critical role in host defense. However, they do not provide compelling evidence, as even the infectious phenotype of patients with mutations in IRAK4 may result from impaired signaling via receptors other than TLRs. Paradoxically, these experiments of nature raise the possibility that the entire set of human TLRs is largely redundant in protective immunity in vivo.