Retinoblastoma (Rb), a tumor suppressor gene, is inactivated in many types of cancer. However little is known about how the loss of Rb function can be targeted in cancer therapies. We have identified that inactivation of TSC2 in Rb mutant cancer cells will induce a synergistic cell death. The synergistic cell death is due to an increase in cellular stress including metabolic, ER, and oxidative stress. Therefore, inactivation of TSC2 and chemothereputics that result in induction of cellular stress may be a novel and effective way to treat cancers containing inactivated Rb.