Prior to the introduction of T cell depletion graft-versus-host disease (GVHD) was the major cause of transplant-related mortality. Why has the remarkable technical achievement of efficient T cell depletion, which has virtually eliminated severe GVHD over the last few years, failed to reduce mortality and increase disease-free survival? This review examines the value of T cell depletion based on recent clinical experience. It surveys the directions that are being pursued in an effort to solve the problems that have arisen and indicates how this is leading to a greater understanding of the mechanisms involved in GVHD and the graft-versus-leukaemia effect.