The PI3K pathway is a key regulator of metabolism, of cell proliferation and migration and some of its components (Eg. PIK3CA and PTEN) are frequently altered in cancer by genetic events that deregulate its output. However, PI3K signaling is not usually the primary driver of these tumors and inhibitors of components of the pathway have only modest antitumor effects owing to drug acquired resistance, improper scheduling and dosage of drugs etc. Negative feedbacks are the major regulators of homeostasis in signaling networks and are relieved on inhibiting the PI3K pathway, contributing to the adaptive resistance. We found that continuous long-term treatment with PI3K inhibitors mounts an adaptive response that becomes more stable as a function of duration of inhibition upon drug removal and is associated with increased growth rate and decreased sensitivity to PI3K inhibitors on re-treatment, supporting the rationale of an intermittent as opposed to continuous treatment regimen involving PI3K inhibitors. Several feedback loops exist within the PI3K pathway but none have been associated with its primary negative regulator PTEN. We now show that both physiologic and oncogenic activation of the PI3K signaling cause an increase in the expression of the lipid phosphatase PTEN, thus limiting the duration of the signal and the output of the pathway in tumors. Pharmacologic and physiologic inhibitions of the pathway reduce PTEN, thus buffering the effects of inhibition and contributing to the rebound in pathway activity that occurs in tumors treated with PI3K pathway inhibitors. Regulation of expression is due to mTOR/4EBP1 dependent control of PTEN translation and is lost when 4EBP1 is knocked out. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in 1) reducing the output of oncogenic mutants that dysregulate the pathway, 2) reducing the duration of PI3K signaling on growth factor stimulation, 3) reducing the antitumor activity of PI3K pathway inhibitors, and 3) perhaps, in mediating insulin resistance.