NSD2, a histone lysine methyltransferase, is overexpressed as a result of the t(4;14) translocation that is associated with 15-20% of multiple myeloma. Earlier studies have indicated that NSD2 may be involved in myelomagenesis and suggested that it may be a target for myeloma therapy. Here we show that NSD2 is required for clonogenic growth, adherence and proliferation on bone marrow stroma, and tumorigenesis of t(4;14)+ but not t(4;14)- myeloma cells, in a methyltransferase activity dependent manner. Furthermore, we found that PHD domains are important for NSD2 cellular activity and biological functions by recruiting it to oncogenic gene loci and driving downstream transcription activation events. These results strengthened the disease link of NSD2 and provided a basis that targeting NSD2 may be a therapeutic strategy in multiple myeloma patients with t(4;14) translocation. Our data also revealed multiple domains in the protein for possible chemical modulation.