The development of novel therapies for multiple myeloma (MM) depends on a comprehensive understanding of the events leading to cellular proliferation and survival. Controlling pathways that regulate growth signals is an emerging and complementary approach to myeloma treatment. Dysregulation of the phosphotidylinositol 3-kinase (PI3K)/Akt pathway has been implicated in malignant transformation and progression of a number of cancers, including MM. 1–10 When activated, the PI3K/Akt pathway leads to downstream activators of cellular proliferation, adhesion, migration, survival, angiogenesis, and drug resistance (Fig. 1). 11, 12 The PI3K/Akt pathway is a central gatekeeper for these critical cellular functions. Established proteins and genes such as mTOR (mammalian target of rapamycin), p53, NF-κB (nuclear factor kappa B), and BAD (Bcl-2 antagonist of cell death) are all regulated through PI3K and Akt activation, making them attractive targets for broad downstream effects. Direct PI3K inhibition has demonstrated impressive tumor inhibition and regression in cell line and animal models, and multiple agents including SF1126 are currently in clinical trials. Drugs such as perifosine that are specific for Akt are also in development. Combinations of these agents with existing therapies are rational approaches on the path to improving myeloma treatment.