Different parts of the skin respond to ionizing radiation with different sensitivities. To examine the mechanisms underlying these different responses, we investigated various cellular parameters in the skin after exposure of mice to 5 Gy of ionizing radiation. Epidermal cells responded to radiation by undergoing growth arrest, whereas the cells in the matrix of hair follicles underwent apoptosis but not growth arrest. These distinct responses correlated with differential increases in p53 and p21 proteins in these two populations of cells; whereas an increase in p53 protein levels was observed in both epidermis and hair follicular matrix, especially in the latter, the induction of p21 was strong in the epidermis but absent in the follicular matrical cells. Studies using p53-null and p21-null mice demonstrated that the radiation-induced apoptosis in the hair follicles was fully dependent on p53, and growth arrest in the epidermis was only partially dependent on p53 but fully dependent on p21. These results indicate that two epithelial cell types respond to radiation by different pathways that are governed in part by the differential p53- and p21-dependent responses of these cells; high-level induction of p53 in the absence of p21 induction led to apoptosis, whereas intermediate induction of both p53 and p21 led to growth arrest.