The substantial progress in our understanding of molecular and cellular biology has allowed us to design biological therapeutics ('biologicals') with defined targets and effector functions. These biologicals have greatly contributed to our current knowledge of pathogenetic mechanisms in autoimmune diseases. However, although some of the biologicals have been extremely successful in treating the symptoms of chronic inflammation, biological therapy has not yet met the expectations of permanently silencing the chronic immune response. In this commentary we discuss current concepts and future directions of biological therapy, and the potential usefulness of biologicals as a treatment of human autoimmune diseases in appropriate critical applications with the use of suitably designed agents.