The TSC1 and TSC2 tumor suppressor genes were initially identified as human disease genes mutated in tuberous sclerosis, a syndrome characterized by the widespread development of benign tumors. TSC2 encodes a putative GTPase activating protein (GAP), while TSC1 encodes a novel protein containing two coiledcoil domains. Recent genetic studies in Drosophila have implicated Tsc1 and Tsc2 as negative regulators of TOR signaling in cell growth, with a loss of Tsc1/Tsc2 leading to increased cell size. In animal cells, loss of Tsc1/Tsc2 leads to an increase in S6K activity that is sensitive to rapamycin but resistant to amino acid starvation. Genetic and biochemical studies in Drosophila further identified Rheb, a member of the Ras superfamily GTPases, as a direct target of the GAP activity of Tsc2 that functions between Tsc1/Tsc2 and TOR. These exciting developments demonstrate that Drosophila is a powerful system to decipher the architecture of the TOR signaling network at molecular, cellular and organismal levels.