Recent studies have revealed remarkable species specificity of the Toll-like receptors (TLRs) TLR11 and TLR12 and the immunity-related GTPase (IRG) proteins that are essential elements for detection and immune control of Toxoplasma gondii in mice, but not in humans. The biological and evolutionary implications of these findings for the T. gondii host-pathogen relationship and for human disease are discussed. •Mice, unlike humans, are evolutionarily significant hosts for T. gondii•Mouse immune system and T. gondii coadapted to selective pressures on each other•TLR11, TLR12, and IRG proteins present a remarkable host and pathogen specificity•Sensing and control of T. gondii in mice requires TLR11, TLR12, and IRG proteins