The introduction of novel agents, such as bortezomib, thalidomide, and lenalidomide, into daily practice has dramatically improved clinical outcomes and prolonged survival of patients with multiple myeloma (MM). However, despite these advanced clinical benefits, MM remains an incurable hematological malignancy. Therefore, development of new agents and novel therapeutic strategies is urgently needed. Recent advances toward understanding the mechanism of myeloma cell growth and drug resistance in the bone marrow milieu have provided clues for the development of next-generation agents aimed at improving patient outcomes. In this review article, we discuss new possible agents for the treatment of MM based on recent advances in the understanding of signaling pathways in myeloma cells.