Cyclophilins (CYPs) are a group of highly conserved proteins involved in host-pathogen interactions in diverse plant species. However, the role of CYPs during disease resistance in wheat remains largely elusive. In the present study, the systematic genome-wide survey revealed a set of 81 genes from three subfamilies (GI, GII, and GIII) distributed on all 21 wheat chromosomes. The gene structures of P members were found to be highly variable, with 1-14 exons/introns and 15 conserved motifs. A network of miRNA targets with demonstrated that were targeted by multiple miRNAs and vice versa. Expression profiling was done in leaf rust susceptible Chinese spring (CS) and the CS- derived resistant IL "Transfer (TR). Three homoeologous genes (24, 31, and ) showed high expression and three homoeologous genes (, , and ) showed low expression in TR relative to Chinese Spring. Most of the other TaCYPs showed comparable expression changes (down- or upregulation) in both contrasting TR and CS. Expression of 16 s showed significant association ( < 0.05) with superoxide radical and hydrogen peroxide abundance, suggesting the role of in downstream signaling processes during wheat-leaf rust interaction. The differentially expressing s may be potential targets for future validation using transgenic (overexpression, RNAi or CRISPR-CAS) approaches and for the development of leaf rust-resistant wheat genotypes.