Primary therapy of acute GvHD grade II-IV is still based on the systemic application of corticosteroids at doses of 1-2 mg/kg (e.g. prednisolone). Typically, investigators combine this approach with therapeutic doses of calcineurin inhibitors, which are used as prophylactic regimens. Patients not responding to steroids within 5-7 days or those with progressive disease within 72 hours represent a high-risk population that requires further immunosuppressive escalation. Pharmacological second-line therapy is mainly based on centre policies and individual decisions since no strategy has been associated with an improvement in survival within a controlled prospective trial. Compounds with efficacy in phase II trials are mycophenolate mofetil, methotrexate, pentostatin, mTOR inhibitors, antibodies targeting TNF-alpha or IL-2 pathways, and monoclonal or polyclonal anti-T cell antibodies. Non-pharmacological options include extracorporeal photopheresis and the infusion of allogeneic mesenchymal stromal cells. For most interventions, earlier treatment (e.g., within two weeks) is associated with a better outcome. However, the overall effcacy and toxicity of most approaches are unsatisfactory. Future developments include the use of regulatory T cells and more targeted approaches using small molecules interacting with specific signalling pathways of antigen-presenting and effector cells.