Psoriasis (PsO) is a common, systemic, chronic inflammatory disease characterized by key clinical symptoms, including itching, pain, and scaling, and is associated with substantial physical, psychosocial, and economic health burdens. Currently, there is no cure for PsO; however, the introduction of biologic therapies has revolutionized the clinical management of patients with PsO by expanding treatment options to include multiple therapies with different mechanisms of action targeting cytokines, including tumor necrosis factor inhibitors (TNFis), interleukin (IL)-17A inhibitors, an IL-12/23 inhibitor, and IL-23 inhibitors. TNFis are historically considered the first-line biologic treatment and the first-generation biologics; however, increased understanding of TNF-α and IL-17 synergistic functions have recently led to evidence that specifically targeting IL-17 may be more likely to improve disease activity than a more general, nonspecific therapy target, such as TNF-α. This review highlights currently available evidence and demonstrates the differences between TNFis and IL-17A inhibitors in patients with PsO with regard to efficacy and safety.