Psoriasis is perhaps unique for a disease studied through translational science in that there is not an accepted animal model, yet many rounds of bidirectional translation have taken place that have helped to define disease pathogenesis and to advance therapy. In this review, we illustrate the evolution of new pathogenic concepts and the testing of new therapeutic agents through translational research in humans. We present a current view of disease pathogenesis that stems from research in patients and animal models, but with the perspectives (i) that disease models can advance or hinder the overall translational enterprise and (ii) that the research process must be firmly grounded in the pathophysiology of the actual human condition.