The procedure of hematopoietic stem cell transplantation (HSCT) will keep expanding over the next decades. The list of indications for autologous or allogeneic HSCT of nonmalignant and malignant hematological disorders will grow. Other life-threatening diseases such as genetic, metabolic or autoimmune disorders including systemic sclerosis will undergo critical evaluation for that treatment. As a consequence of continuous research and clinical progress in that field, more and more patients will survive HSCT, and physicians will be confronted with organ-specific late and very late effects including chronic graft-versus-host disease (cGVHD). Changes of eligibility criteria for HSCT, quality assessment of the stem cell graft, graft manipulation, and new developments in donor selection might possibly impact patients' health status and epidemiology as well as presentations of posttransplant complications. Efforts to diminish GVHD while forcing graft-versus-tumor effects will persist to be one of the major goals, and advances in prophylaxis and treatment of cGVHD will remain high priority. Changes in stem cell sources and graft manipulation might have additional influence on immune reconstitution and posttransplant disorders of infectious and immunological type. The recent publications of the National Institutes of Health consensus development project on various aspects of chronic GVHD has rightly positioned cGVHD as a serious and difficult to treat pleiotropic systemic disease with tremendous impact on long-term outcome. In this chapter, we will point out some of the most important issues and trends related to HSCT. Copyright © 2012 S. Karger AG, Basel.