The concept of biological therapy arises from the specific targeting of a factor, e.g. a cytokine, involved in the inflammatory cascade. Thus, biologicals disrupt the complex network of autoimmune-inflammatory events. Today, rheumatoid arthritis is a prototype disease in this context as most compounds have been tried in this disease. Recently, biological therapy has been introduced to the treatment of other diseases including various forms of arthritis, such as ankylosing spondylitis and psoriatic arthritis, as well as systemic autoimmune disorders, such as systemic lupus erythematosus, scleroderma, inflammatory myopathies and Sjogren's syndrome. Anti-tumor necrosis factor-alpha (TNF-alpha) agents play a central role in biological therapy as these agents have been successfully tried in most of these diseases. When seeking for specific targets for biologicals, pathogenic factors of the disease, such as Th1 or Th2 type responses, should be evaluated. Some mostly T-cell mediated diseases, such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, polymyositis, polyarticular juvenile arthritis respond well to anti-TNF agents and T cell targeting, while others, such as lupus, Sjogren's syndrome, dermatomyositis may rather respond to anti-B cell biologicals. In this review, authors discuss the most recent advances in the biological therapy of arthritis and systemic autoimmune diseases including issues of efficacy and safety.