Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, occurring in about one third of psoriasis patients, and exhibiting very varied clinical manifestations and comorbidities. Although the clinical outcome of the disease has been significantly improved recently, mainly due to utilization of novel agents targeting the IL-23/-17 axis, unmet needs still exist. Emerging insights into the disease’s pathogenesis led to development of new drugs acting against critical molecular targets and their efficacy in psoriasis and/or PsA has been tested in Phase III clinical trials. Some of these therapeutic regimens have been already approved; some look promising but others have been proven inefficacious. Future studies are expected to determine the place of these compounds within the therapeutic algorithm of PsA. In this chapter we describe the rationale and clinical impact of incorporating small molecules in PsA treatment, as well as specific molecules involved in pathogenesis that may serve as therapeutic targets.