Contrary to immune cells, the response of the kidney structural cells in rejection is less established. We performed single-cell RNA sequencing of 18 kidney transplant biopsies from 14 recipients. Single-cell RNA sequencing identified cells from the major compartments of the kidney, next to infiltrated immune cells. Endothelial cells from the glomerulus, peritubular capillaries, and vasa recta showed upregulation of class I and II human leukocyte antigen genes, adhesion molecules, cytokines, and chemokines, suggesting active participation in the alloimmune process, with compartment-specific differences. Epithelial cells including proximal tubular, loop of Henle, and collecting duct cells, also showed increased expression of immune genes. Strikingly, in proximal tubule cells, a strong downregulation of energy metabolism upon inflammation was observed. There was a large overlap between the cell-specific expression changes upon alloimmune inflammation and those observed in 2 large microarray biopsy cohorts. In conclusion, the kidney structural cells, being the main target of the alloimmune process, appear to actively contribute herein, enhancing the damaging effects of the infiltrating immune cells. In epithelial cells, a profound shutdown of metabolism was seen upon inflammation, which is associated with poor kidney function. These observations highlight the critical role of the graft in triggering and sustaining rejection after transplantation.