A large-scale retrospective study of 438 adenoid cystic carcinoma (ACC) cases validates the prognostic and therapeutic relevance of two molecular subtypes: ACC-I, characterized by MYC overexpression and frequent NOTCH1 mutations, and ACC-II, defined by TP63 upregulation and receptor tyrosine kinase pathway activation. Here, TP63 is linked to adrenal cortex carcinoma.