The epidermal growth factor receptor (EGFR) system is an established regulator of the development and homeostasis of the hair follicle and interfollicular epidermis. Here, we evaluated EGFR actions on the sebaceous glands (SGs) by employing Dsk5 mice, a mutant line in which the EGFR is constitutively activated in a ligand-independent manner. Compared to control littermates, Dsk5 mice showed increased sebum levels and enlarged SGs, which contained a higher number of cells and showed stronger proliferation. c-myc transcript levels were increased in Dsk5 skin, suggesting that c-myc mediates the proliferative stimuli of the EGFR in the SG. Analysis of differentiation markers revealed deregulated expression of Scd1 and Scd3, indicating that sebaceous lipogenesis is affected in Dsk5 mice. In conclusion, our study indicates that the EGFR is an important regulator of presebocyte proliferation, contributing to the final cell number, to the size and to the lipid output of SGs.