The introduction of stem cell transplantation and the novel anti-myeloma agents, bortezomib, thalidomide, and lenalidomide, have improved the outcome of patients with multiple myeloma. These advances have transformed myeloma into a chronic condition, with multiple relapses and salvage therapies, all of which result in cumulative immunosuppression and higher risk of infection. In addition to the immunodeficiency related to myeloma and its complications, the type of anti-myeloma therapy used also plays a role in the development of infection. Therapy with bortezomib increases the risk for reactivation of herpes simplex and herpes zoster viruses, whereas the application of stem cell transplantation has broadened the spectrum of infection to include those caused by Clostridium difficile, cytomegalovirus, and opportunistic moulds. Key to the management of infection is the understanding of the specific risk factors and periods during which patients are at risk; this allows the anticipation of the likely pathogen(s) and the application of risk-adjusted prophylactic and treatment strategies.