SummaryIn Arabidopsis, RPP4 confers resistance to Peronospora parasitica (P.p.) races Emoy2 and Emwa1 (downy mildew). We identified RPP4 in Col‐0 as a member of the clustered RPP5 multigene family encoding nucleotide‐binding leucine‐rich repeat proteins with Toll/interleukin‐1 receptor domains. RPP4 is the orthologue of RPP5 which, in addition to recognizing P.p. race Noco2, also mediates resistance to Emoy2 and Emwa1. Most differences between RPP4 and RPP5 occur in residues that constitute the TIR domain and in LRR residues that are predicted to confer recognition specificity. RPP4 requires the action of at least 12 defence components, including DTH9, EDS1, PAD4, PAL, PBS2, PBS3, SID1, SID2 and salicylic acid. The ndr1, npr1 and rps5‐1 mutations partially compromise RPP4 function in cotyledons but not in true leaves. The identification of RPP4 as a TIR‐NB‐LRR protein, coupled with its dependence on certain signalling components in true leaves, is consistent with the hypothesis that distinct NB‐LRR protein classes differentially signal through EDS1 and NDR1. Our results suggest that RPP4‐mediated resistance is developmentally regulated and that in cotyledons there is cross‐talk between EDS1 and NDR1 signalling and processes regulating systemic acquired resistance.