Autoimmune diseases are a heterogeneous group of disorders and epidemiological studies demonstrate that their incidence is increasing worldwide. It is known that a complex interaction of genetic and environmental factors underlies their complex etiopathogenesis. In the light of the aforegoing the exact molecular key events were difficult to be explored; these represent the leading step to the prevention and treatment of autoimmune disorders. Novel therapeutic approaches are nowadays under investigation and specific treatments have been preferentially applied in experimental models of disease. New results were brought about and fascinating new pathways for treatment of autoimmunity were launched in the past years. Nevertheless novel targets for intervention, revealed to be successful in animal models, were not necessarily proven to be successful in humans, therefore were not necessarily introduced in clinical trials. In this review we present and discuss the results of novel therapeutic approaches and novel experimental strategies including antagonists of cytokines and cytokine receptors, Toll like receptors inhibitors, proteasome inhibitors, antisense oligonucleotides vehicled by nanocarriers, inhibitors of leukocyte migration, kinase inhibitors. We also present the results of ongoing trials in humans that rely on novel biologicals agents. These are presented as applied to organ and non-organ specific autoimmune disorders. In the future, novel therapeutic strategies will also combine different drugs that possibly intervene at different levels in which the immune system may be halted in its function.