Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately 2% of the world's population. In this guideline, we focus the discussion on systemic, non-biologic medications for the treatment of this disease. We provide a detailed discussion of efficacy and safety for the most commonly used medications-including methotrexate, cyclosporine, and acitretin-and provide recommendations to assist prescribers in initiating and managing patients on these treatments. Additionally, we discuss newer therapies, including tofacitinib and apremilast, and briefly touch upon a number of other medications, including fumaric acid esters (used outside the US) and therapies that are no longer widely used for the treatment of psoriasis, i.e. hydroxyurea, leflunomide, mycophenolate mofetil, thioguanine, and tacrolimus.