Allogeneic HSCT is performed for a small number of inborn errors of metabolism (IEM). Over the last years, transplantation outcomes have improved in this group of patients as the factors that predicted for poor transplantation outcomes were understood and addressed. The role of transplantation and its potential benefit for an individual patient with a certain IEM is therefore now much better defined. In parallel with improvements in transplantation techniques, other therapies such as pharmacological enzyme replacement therapy (ERT), substrate inhibition, and gene therapy have been developed and are increasingly available to clinicians and their patients. This review covers the following areas: (1) the scientific principles that underpin transplantation in IEM; (2) the variables of the transplantation process itself that predict for successful outcome in terms of engrafted survival after HSCT; (3) the reasons that some apparently phenotypically similar disorders might respond very differently to transplantation therapy; (4) the factors that currently influence the response of a particular patient with a particular disease to allogeneic transplantation, and how these factors might be manipulated in the future to further improve transplantation outcomes in different metabolic illnesses; and (5) how other therapeutic modalities, including ERT, gene therapy, and substrate reduction therapy, might complement and compete with HSCT in the coming years.