The last decade has witnessed a significant advance in the management of refractory moderate-to-severe psoriasis. This advance is the introduction of biological therapies to clinical practice. Three classes of biological therapies have been used. Of the first 2 classes to be introduced, the T-cell inhibitors and tumor necrosis factor (TNF)-alpha inhibitors, there have been differing fates with one of the T-cell inhibitors, efalizumab, being withdrawn because of a rare, unpredictable association with a usually fatal neurological condition, progressive multifocal leukoencephalopathy. In contrast, anti-TNF treatments are now firmly established offering a high level of efficacy and a good safety record across several indications, including psoriasis. A new approach involves targeting the p40 subunit, common to interleukins 12 and 23. Ustekinumab, the first drug in this class, now offers a viable alternative to anti-TNFs in the treatment of moderate-to-severe psoriasis. In this article, we discuss approaches that may be utilized to refine these existing therapies and examine future therapeutic targets for biological therapies.