High-dose chemotherapy and autologous stem cell transplantation (SCT) or allogeneic SCT can lead to durable remissions in patients with hematologic malignancies. In the mid-1980s the first studies demonstrating the use of peripheral blood stem cells (PBSC) for autologous transplantation instead of bone marrow (BM) were performed. Subsequently, PBSC have largely supplanted BM, and are, in part, the reason for the decline in procedural related toxicity of autologous SCT [1]. In the allogeneic setting, the use of reduced-intensity conditioning (RIC), and better graft-versus-host disease (GVHD) prophylaxis has reduced treatment-related mortality (TRM). Initial transplant studies were limited to younger patients and those without significant infections such as HIV. However, there have been advances in HIV care. For example, the advent of protease inhibitor-based highly active antiretroviral therapy (HAART) and improved infection prophylaxis have greatly improved survival in HIV-infected patients. This has led to the paradigm of HIV as a ‘‘chronic condition’’ akin to diabetes that should not preclude autologous transplant. Furthermore, now that the toxicity of autologous and allogeneic transplant decreased, transplant is feasible in older patients, and, therefore, arbitrary age cutoffs may exclude patients from a potentially curative procedure. Other methods of risk stratification such as the comorbidity index can provide a more accurate assessment of transplant-related risk and help in the determination of appropriate conditioning regimens. Herein we review the data on SCT in these ‘‘vulnerable’’ patients, that is, those with HIV infection and elderly patients, and we will also discuss the use of the comorbidity index and how it can aid in the decision-making process for patients by optimizing