Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by diffuse bone marrow (BM) infiltration, hepatosplenomegaly, lymphadenopathy, and the presence of a serum IgM monoclonal protein. Clinically, patients may present with fatigue, weight loss, peripheral neuropathy or symptoms of hyperviscosity, including headache, blurred vision or epistaxis. WM is an indolent disease, although it remains incurable with a median survival of five to six years. There are no FDA-approved drugs specifically for the treatment of WM, but chemotherapeutic agents used extensively in WM include alkylating agents (chlorambucil and cyclophosphamide) or nucleoside analogs (fludarabine), alone, or in combination with corticosteroids. However, these agents are limited by their toxicity profiles, low efficacy, and adverse effect on future stem cell harvesting. In addition, patients with relapsed/refractory disease are still in need of novel therapeutic options. As a result, there has been strong interest in discovering and translating targeted therapies in WM. The prototype for this is rituximab, the anti-CD20 mAb that specifically targets B-cells and has become one of the main treatment options in WM. Several new targeted therapies have been tested preclinically in WM, with diffuse molecular targets, including the ubiquitin-proteasome pathway, PI3-kinase/Akt and mTOR signaling pathways, as well as the BM microenvironment. These studies have resulted in several new promising clinical phase trials in WM over the last five years, providing hope for shifting the treatment paradigm in WM. In this review, the novel therapeutics that target these pathways are discussed.