Psoriasis is a chronic, inflammatory, immune-mediated skin disease that affects roughly 2% of adults in the United States. The immunopathogenic pathways associated with psoriasis are complex, and to effectively target the underlying cytokine networks involved in disease progression, drugs are needed that act on specific components of the immune system. As understanding of the role of proinflammatory signaling molecules in the psoriatic disease process has evolved, several biologic agents have been engineered to block key cytokines associated with psoriasis. Recently, improvements in the understanding of the pathogenesis have led to the development of agents that may target the mechanism of disease more directly. This review describes the immunopathogenesis of psoriasis and how targeting disease-specific mechanisms with biologic agents may improve clinical outcomes and potentially result in better safety profiles than conventional agents. Results from pivotal clinical studies evaluating the efficacy and safety of approved tumor necrosis factor-α antagonists (etanercept, infliximab, and adalimumab) and the interleukin-12/23 inhibitor ustekinumab are summarized. In addition, we include clinical findings to date evaluating a new class of biologics that neutralize interleukin-17A (secukinumab, ixekizumab) or act as an interleukin-17 receptor antagonist (brodalumab). Finally, this review discusses efficacy and safety factors, as well as patient characteristics to consider, when selecting a biologic agent for psoriasis disease management.