Golovinomyces orontii is an obligate biotrophic powdery mildew (PM) that colonizes Arabidopsis thaliana and agronomic species. It establishes a specialized feeding structure in epidermal cells to fuel its extensive surface hyphal growth and reproduction. Previously, endoreduplication was identified in Arabidopsis mesophyll cells underlying the fungal feeding site, presumably to meet the metabolic demands imposed by the fungus. Furthermore, the cell cycle transcription factor MYB3R4 was shown to regulate this process. Herein, PM-induced endoreduplication is further characterized and three additional factors influencing host ploidy in cells underlying the fungal feeding site are identified. While mutations in PUX2 and PMR6 reduce basal ploidy, mutations in PMR5 (and MYB3R4) abrogate the PM-induced ploidy increase. Moreover, analysis of pmr5 microarray data suggests that PMR5 acts upstream of a MYB3R transcription factor such as MYB3R4 to control PM-induced ploidy. Induced endoreduplication occurs exclusively in mesophyll cells underlying the fungal feeding site at 5 days postinoculation, concomitant with PM reproduction. Gene copy number increases and chromatin remains decondensed, suggesting active, elevated gene expression. Cell ploidy underlying the fungal feeding site is highly correlated with the extent of PM growth and reproduction for these mutants, indicating that (induced) mesophyll cell ploidy is a PM susceptibility determinant.