Advances in the treatment of moderate-to-severe plaque psoriasis, including new biological agents and related drugs, are reviewed. Most patients with psoriasis have mild disease that can be treated with topical agents alone; however, over one third of patients have more-extensive disease, called moderate-to-severe plaque psoriasis. Although effective, traditional therapies, including methotrexate, cyclosporine, acitretin, and phototherapy, have serious adverse effects that limit both the initiation and duration of treatment, necessitating sequential treatment regimens. With the increasing knowledge of the immune nature of the disease, biological agents that target T lymphocytes, tumor necrosis factor (TNF)-α, interleukin (IL)-12, and IL-23 have been used successfully in moderate-to-severe psoriasis. Etanercept, adalimumab, and infliximab are also highly effective in the treatment of moderate-to-severe plaque psoriasis. Ustekinumab, a new agent that targets IL-12 and IL-23, was approved for marketing in 2009 and offers similar efficacy and safety profiles to the anti-TNF agents. While the rapid onset and apparent lack of long-term toxicity of biological agents make them major advances in the treatment of more severe forms of psoriasis, the lack of extensive experience with these agents in patients with psoriasis leaves several unresolved issues that must be addressed before their exact place in therapy can be determined. With the development of biological therapies over the past 10 years, health care providers have a much broader choice of highly effective agents with which to treat patients suffering from moderate-to-severe plaque psoriasis. Though costly to use, biological agents offer considerable advantages over previously available systemic therapies.