Waldenström macroglobulinemia (WM) is a rare, indolent, and monoclonal immunoglobulin M-associated lymphoplasmacytic disorder with unique clinicopathologic characteristics. Over the past decade, remarkable progress has occurred on both the diagnostic and therapeutic fronts in WM. A deeper understanding of the disease biology emanates from the seminal discoveries of myeloid differentiation primary response 88 (MYD88) L265P somatic mutation in the vast majority of cases and C-X-C chemokine receptor, type 4, mutations in about a third of patients. Although WM remains an incurable malignancy, and the indications to initiate treatment are largely unchanged, the therapeutic armamentarium continues to expand. Acknowledging the paucity of high-level evidence from large randomized controlled trials, herein, we evaluate the genomic aberrations and provide a strategic framework for the management in the frontline as well as the relapsed/refractory settings of symptomatic WM.