Nucleoside Analogues (NA) are considered as appropriate agents in the treatment of Waldenström's Macroglobulinemia (WM). There are sporadic reports on increased incidence of transformation to high grade non-Hodgkin lymphoma (transformation to NHL) and development of therapy related-myelodysplasia/acute leukemia (t-MDS/AML) among WM patients treated with NA. Several studies have been conducted in Europe and in the United States to retrospectively examine the incidence of such events in WM patients. The incidences of transformation to NHL and t-MDS/AML ranged from 4.7% to 8%, and from 1.4% to 8.9%, respectively, and demonstrated an increased incidence of these late events among WM patients treated with NA. The effect of these secondary malignancies needs to be better evaluated in prospective studies, especially in young patients. These NA treatment-associated risks should not by themselves be used to justify avoidance of NA therapy for WM patients but should be used in considering risk versus benefit for a particular patient given the expanding options of therapy for WM patients.