Psoriasis is one of the most common T cell–mediated autoimmune diseases in humans. Although a role for the innate immune system in driving the autoimmune T cell cascade has been proposed, its nature remains elusive. We show that plasmacytoid predendritic cells (PDCs), the natural interferon (IFN)- α –producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN- α early during disease formation. In a xenograft model of human psoriasis, we demonstrate that blocking IFN- α signaling or inhibiting the ability of PDCs to produce IFN- α prevented the T cell–dependent development of psoriasis. Furthermore, IFN- α reconstitution experiments demonstrated that PDC-derived IFN- α is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN- α represent potential early targets for the treatment of psoriasis.