Purpose of review In this review, we discuss the most important aspects of the role of high-dose melphalan (HDM) and autologous stem-cell transplantation (ASCT) in the treatment of multiple myeloma (MM). Recent findings Almost 40 years after the publication of the first study on safety and efficacy of HDM and ASCT in MM patients, and despite the introduction of several drugs and combinations with various targets on the plasma cell and the surrounding microenvironment, HDM–ASCT still stands as a standard of care for the upfront treatment of newly diagnosed MM patients. Indeed, all attempts to replace HDM–ASCT with novel-agent-based, non-transplant strategies have failed to demonstrate their efficacy, at least in terms of progression-free survival. Summary Despite such a long history in MM, a number of open issues regarding HDM–ASCT still exist, from the choice between using transplant in first-line therapy or at relapse to the use of tandem HDM–ASCT in high-risk patients. With the introduction of more and more effective multidrug regimens and of novel immunotherapeutic approaches, the challenge between transplant and non-transplant is not over yet.