Haematopoietic stem cell transplantation (HSCT) can be a curative procedure for a growing number of paediatric diseases, but as the indications for HSCT grow, so does the need to find suitable stem cell donors. When the preferred option of a genoidentical sibling donor is not available alternative donors, including unrelated adult or umbilical cord blood donors, or haploidentical related donors may be considered. Outcome following alternative donor HSCT has improved over the past 20 years but graft-versus-host disease (GvHD) remains a significant obstacle. T cell depletion (TCD) for non-genoidentical grafts aims to reduce the morbidity and mortality associated with GvHD, but this intervention has not led directly to improved survival due to delayed immune reconstitution and increased infections, graft rejection and increased rates of disease relapse. Limited data from the paediatric population, however, suggest some encouraging results for children undergoing haploidentical HSCT: a move from positive selection of CD34+ haematopoietic stem cells towards negative depletion of specific cell subsets in order to retain useful accessory cells within the graft appears to enhance immune reconstitution and improve disease-free survival. Here we review recent paediatric outcome data for T cell-depleted HSCT, explore the role of serotherapy in conditioning regimens and look at future possibilities to improve outcome, including novel allodepletion techniques, suicide gene therapy and pathogen-specific immunotherapy.