Psoriasis is a chronic, systemic, inflammatory disease that is often associated with serious comorbid conditions such as cardiovascular disease, obesity, and diabetes. Many patients with moderate-to-severe psoriasis receive either no treatment or receive topical therapy only and report dissatisfaction with treatment, poorly managed symptoms, and continued impact of the disease on quality of life. Patients currently receiving topical monotherapy can benefit from systemic therapies, which are more effective in reducing clinical symptoms, achieving treatment efficacy targets, and improving quality of life. An array of systemic treatment options with varying mechanisms of action are available, including conventional and newer oral systemic agents and biologics. Each option presents a unique set of benefits, safety risks, dosing schedules, and monitoring requirements. The aim of the current review is to better optimize treatment outcomes in patients with psoriasis by presenting a rationale for when to consider systemic therapy in this patient population. The authors discuss the barriers to use of systemic agents and highlight the central importance of each patient's perspective when assessing disease severity. Additionally, practical strategies for selecting and safely initiating systemic therapy to optimize the treatment of patients with psoriasis are identified.