Waldenström's Macroglobulinemia (WM) is a rare disease of the elderly with a median age of 63-68 years at diagnosis. Despite recent progress in biological insights and therapeutics, WM remains clinically challenging to diagnose and is difficult to manage with significant morbidity and lack of established curative therapies. Recently, the use of whole-genome sequencing has helped to identify a highly recurrent somatic mutation, myeloid differentiation factor 88 [MYD88] L265P in WM. This has fueled major interest in the field and as newer evidence accumulates, it is clear that that discovery of MYD88 L265P mutation may represent an important breakthrough in understanding the pathogenesis of WM and lymphoproliferative disorders. Recent scientific work in this field has also guided the identification of new targets such as CXCR4 and PI3K-delta that may have major implications in the future treatment of WM. This review discusses the role of MYD88 L265P mutations as well as targets beyond MYD88 in the setting of pathogenesis and development of future rational therapeutic trials focusing on patients diagnosed with WM.