The past decade has witnessed a revolution in our understanding of the biochemical mechanisms that contribute to the survival and proliferation of neoplastic cells. Several of these mechanisms depend on signaling by the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. This pathway integrates signals from multiple receptor tyrosine kinases and regulates many cellular processes, including proliferation, growth, and survival. Because these processes are critical for oncogenic transformation, the PI3K/mTOR pathway is being extensively studied in the hope that it will lead to promising new treatments for hematological malignancies. In the sections that follow, we summarize current understanding of this pathway and the results of recent studies of mTOR inhibitors in lymphoma and leukemia.