The application of high-dose treatment with autologous stem cell transplant(s) has improved survival, when compared to standard treatment, in patients with multiple myeloma. However, this benefit is mostly enjoyed by specific patient subgroups characterized by the absence of high-risk disease features. High-risk features are, first and foremost, the detection of unfavorable cytogenetic abnormalities (chromosome 13 deletion, hypodiploidy and myelodysplastic-type abnormalities in an otherwise typical myeloma karyotype) prior to treatment; elevated serum lactate dehydrogenase and C-reactive protein levels at diagnosis and high beta-2 microglobulin levels prior to transplant also convey poor prognosis, although they account for less variability of the observed outcome than the cytogenetic abnormalities. While high-dose treatment with autologous stem cell transplant(s) can cure a sizable minority of patients with low-risk disease features and significantly prolongs survival in others with similar characteristics, patients with high-risk features are virtually incurable and their survival benefit is much less pronounced. As the tremendous clinical variability of myeloma can now be traced to its underlying genetic abnormalities, routine cytogenetic analysis at diagnosis and relapse are absolutely indicated. Based on this stratification, high-risk patients are excellent candidates for novel therapeutic approaches, such as planned non-myeloablative allogeneic transplants following an autologous transplant.