The introduction of high-dose therapy in the 1990s as well as the development of drugs such as thalidomide, lenalidomide, and bortezomib in the 2000s led to an impressive improvement in outcome of patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Clinical trials conducted in the first ten years of the twenty-first century established as standard therapy for these patients a therapeutic approach including induction, single or double ASCT, consolidation, and maintenance therapy. More recently, incorporating second-generation proteasome inhibitors carfilzomib and monoclonal antibody daratumumab into each phase of treatment significantly improved the efficacy of ASCT in terms of measurable residual disease (MRD) negativity, Progression Free Survival (PFS), and Overall Survival (OS). The availability of techniques such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment allowed the design of MRD-based response-adjusted trials that will define, in particular, the role of consolidation and maintenance therapies. In this review, we will provide an overview of the most recent evidence and the future prospects of ASCT in MM patients.