Conventional non-biologic systemic agents are regarded as second-line therapy for the treatment of moderate-to-severe plaque psoriasis after topical treatments. However, long-term data have highlighted a number of safety concerns associated with their prolonged use. Biologic agents targeting specific immune mediators have emerged as an alternative treatment option for patients with moderate-to-severe plaque psoriasis who are unresponsive to, or intolerant of, non-biologic systemic agents. Although several biologics have demonstrated good efficacy and tolerability in short-term trials, treatment guidelines recommend them as third-line therapies due to a relative lack of long-term safety data. Here, we have reviewed the long-term (≥ 1 year) safety data from randomized controlled trials, open-label extension studies and meta-analyses of etanercept, infliximab, efalizumab, adalimumab, alefacept and ustekinumab in the treatment of adults with moderate-to-severe plaque psoriasis. With the exception of efalizumab, which has been withdrawn from both the European and U.S. markets due to long-term safety concerns, these biologics are generally well tolerated in long-term studies, and offer a viable alternative to conventional non-biologic agents in patients with moderate-to-severe plaque psoriasis.