Multiple myeloma is a plasma cell neoplasm with a median survival of 3 to 5 years. Recent advances have improved patient outlook, but the disease remains incurable. Therefore, continued efforts to develop new therapies that target aberrant signaling pathways are needed. The phosphatidylinositol 3-kinase pathway regulates apoptosis, cell cycle regulation, and tumor proliferation. This pathway is constitutively activated in multiple myeloma and its inhibition induces apoptosis. Advances in understanding the signaling cascades mediating proliferation and survival of multiple myeloma cells have markedly improved the treatment of this disease. In this article, we review the role of the phosphatidylinositol 3-kinase/Akt pathway in the pathogenesis of multiple myeloma and the potential therapeutic implications of targeting this pathway in the treatment of multiple myeloma.