Chronic and excessive inflammation in skin and joints causes significant morbidity in psoriasis patients. As a prevalent T lymphocyte-mediated disorder, psoriasis, as well as the side effects associated with its treatment, affects patients globally. In this review, recent progress is discussed in the areas of genetics, the immunological synapse, the untangling of the cytokine web and signaling pathways, xenotransplantation models, and the growing use of selectively targeted therapies. Since psoriasis is currently incurable, new management strategies are proposed to replace previous serendipitous approaches. Such strategic transition from serendipity to the use of novel selective agents aimed at defined targets in psoriatic lesions is moving rapidly from research benches to the bedsides of patients with this chronic and debilitating disease.