I am a pediatrician and immunologist by training, and have in practice become a human geneticist investigating the immunological basis of childhood infectious diseases. The fundamental question in the field of pediatric infectious diseases is that of interindividual, interfamilial, and interpopulation clinical heterogeneity in the course of primary infection: why do only a small minority of infected children develop clinical diseases? This question was first posed around 1910 and has yet to be answered for most infectious diseases and children. The microbe is necessary, but not sufficient for disease development, so what other factors are involved? Contrary to the prevailing view, the pathogenesis of severe pediatric infectious diseases remains obscure. According to the genetic theory of infectious diseases, human germline genetic variability leads to clinical variability; infectious diseases of childhood are thus also genetic traits. From the 1950s until recently, it was thought that mutations in a single gene conferred susceptibility to multiple infectious diseases (one gene, multiple infections), with common infections instead being associated with the inheritance of multiple susceptibility genes (multiple genes, one infection). We hypothesized that severe infectious disease of childhood result from collections of rare single-gene inborn errors of immunity. We have identified and characterized a new group of genetic defects that predispose otherwise healthy children and young adults to a single type of infection (one gene, one infection), a new causal relationship modifying a paradigm that has prevailed in this field for decades. We have deciphered the molecular, cellular, and immunological basis of various infectious diseases, including mycobacterial diseases (mutations in IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, NEMO, IRF8, CYBB, ISG15, TYK2), invasive pneumococcal disease (NEMO, IKBA, IRAK4, MYD88, HOIL1, RPSA, TIRAP), herpes simplex encephalitis (UNC93B1, TLR3, TRAF3, TRIF, TBK1), chronic mucocutaneous candidiasis (IL17F, IL17RA, IL17RC, STAT1, ACT1), dermatophytic disease (CARD9), Kaposi sarcoma (OX40), severe flu (IRF7), and invasive staphylococcal disease (TIRAP). These studies are not merely a reductionist catalog of genes; they have defined, in a holistic manner, the molecular, cellular, and immunological pathways controlling these microganisms. These studies have important clinical implications, as they provide a basis for genetic counseling and a rationale for developing new therapeutic approaches based on an understanding of the host component of infectious diseases. These studies also have major biological implications, as they reveal the largely redundant function of host defense genes in natura, in the setting of a natural ecosystem governed by natural selection.