The mechanisms by which mammalian epidermal stem cells cease to proliferate and embark upon terminal differentiation are still poorly understood. By conditionally ablating two highly expressed transcription factors, AP-2α and AP-2γ, we unmasked functional redundancies and discovered an essential role for AP-2s in the process. In vivo and in vitro, AP-2 deficiency is accompanied by surprisingly minimal changes in basal gene expression but severely perturbed terminal differentiation and suppression of additional transcription factors and structural genes involved. In dissecting the underlying molecular pathways, we uncover parallel pathways involving AP-2 and Notch signaling, which converge to govern CCAAT/enhancer binding protein genes and orchestrate the transition from basal proliferation to suprabasal differentiation. Finally, we extend the striking similarities in compromising either Notch signaling or AP-2α/AP-2γ in developing skin to that in postnatal skin, where all hair follicles and sebaceous gland differentiation are also repressed and overt signs of premalignant conversion emerge.