Multiple myeloma is the second most hematological malignancy, accounting for more than 10% of all blood cancers and 2% of annual cancer-related deaths due to lack of curable drugs. Novel and molecularly targeted anti-MM drugs are in urgent need. The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a critical regulatory role in multiple myeloma pathophysiology, including survival, proliferation, migration, angiogenesis, as well as drug resistance, and has emerged as a key therapeutic target. Many potent inhibitors targeting this pathway have been developed and some have been moved for clinical evaluations for multiple myeloma. In this review, we highlighted the role of the PI3K/AKT pathway in the pathogenesis of multiple myeloma, and current advances in drug discovery for this class of inhibitors. Discovery strategies toward the PI3K/AKT inhibitors were also discussed.