The refinement of transplantation procedures and the development and application of novel agents has improved outcomes for patients with multiple myeloma, resulting in a shift of focus from disease stabilisation to attainment of complete response (CR). More recently, depth of response has been shown to exhibit prognostic significance in multiple myeloma; studies have reported significantly longer progression-free survival (PFS), overall survival, time to progression, and duration of response in patients who achieve CR compared with those who do not. This has been demonstrated in newly diagnosed disease (transplant-eligible and -ineligible patients), progressive or relapsed/refractory multiple myeloma, and following a variety of interventions. As increasingly effective therapies allow more patients to achieve deeper responses, new classifications have been endorsed: stringent CR, immunophenotypic CR, and molecular CR. However, even patients who respond to therapy may go on to relapse, possibly due to the presence of minimal residual disease (MRD) undetected by morphological assessment of bone marrow alone. The three main assays for detecting MRD in multiple myeloma are multiparameter flow cytometry (MFC), allele-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-PCR), and high-throughput sequencing. While these techniques differ in applicability, sensitivity, specificity, ease of use, and turnaround time, concordance rates between high-throughput sequencing and MFC of 83% and between high-throughput sequencing and ASO-PCR of 85% have been reported. The presence or level of MRD has been shown to predict outcomes in patients who have responded to therapy, including those who have achieved a CR. In the Myeloma IX trial, a significantly longer PFS was observed among intensively treated patients who were MRD-negative (by MFC) versus patients who were MRD-positive (median 28.6 vs 15.5 mo.; p<0.001); this was also true in patients who achieved CR (34.3 vs 14.1 mo.; p=0.007). In a prospective study in Spain, elderly patients who were ineligible for transplantation who attained an immunophenotypic CR (by MFC) also exhibited superior PFS versus patients who attained stringent or conventional CR. With increasing evidence of the prognostic implications of depth of response and improved detection techniques, eliminating MRD may become the new goal of myeloma therapy.