Despite the application of allogeneic stem cell transplantation (SCT) since 1957 we have not been able to eradicate Graft versus Host Disease (GVHD) as a significant contributor of treatment related mortality (TRM) and morbidity. In the last years, much progress has been made in unravelling the complex pathophysiology of GVHD. These insights have led to new therapies and will hopefully further contribute to complete eradication of GVHD. Unfortunately we are not there yet and as hematologists we still have to counsel our patients about the complex risks involving allogeneic SCT. In this thesis we conducted two clinical trials and analyzed data, clinical parameters as well as soluble and cellular markers, to provide insight into the pathophysiology of GVHD. Our clinical study with Mesenchymal Stromal Cells (MSC) in steroid refractory acute GVHD patients showed a complete response rate of 50% which associates with superior overall survival. Patients treated with MSC derived from very young bone marrow donors also show improved overall survival compared to patients treated with older bone marrow donors. In patients with sclerotic chronic GVHD we tested the new combination of rituximab and nilotinib that showed promising results with response rates of 71% including 2 patients achieving a complete response. Therapeutic drug monitoring of nilotinib concentrations could possibly further enhance this effect. The combination strategy of B-cell depletion and tyrosine kinase inhibition has already been adopted in current clinical practice.