The nature of the trophic response of the mouse submandibular gland to thyroxine (T4) was examined. Adult female Swiss- Webster mice were given daily subcutaneous injections of T4 (1 μg/gm body weight) for two or four days; two injections of tritiated thymidine (3H- TdR) were given 24 and 29 hours after the last injection of hormone, and the mice were killed one hour after the last injection of 3H- TdR. One gland was analyzed chemically for DNA content and for incorporation of 3H- TdR, while the other was used to prepare autoradiograms. The cellular composition of each gland was analyzed by counting 1000 nuclei, and the frequency and labelling index (LI) of six cell types were established. A rise in specific activity of DNA and a fall in its concentration were seen in response to T4. The LI for the entire gland more than doubled. The LIs and frequencies of granular convoluted tubule and granular intercalated duct cells were increased more than those of acinar and nongranular intercalated duct cells; striated and excretory duct cells were not affected. It is concluded that the enlargement of the submandibular gland of the mouse caused by T4 is due to both hyperplastic and hypertrophic effects.