The reduction of intracellular 1, 4, 5-inositol trisphosphate (IP 3) levels stimulates autophagy, whereas the enhancement of IP 3 levels inhibits autophagy induced by nutrient depletion. Here, we show that knockdown of the IP 3 receptor (IP 3 R) with small interfering RNAs and pharmacological IP 3 R blockade is a strong stimulus for the induction of autophagy. The IP 3 R is known to reside in the membranes of the endoplasmic reticulum (ER) as well as within ER–mitochondrial contact sites, and IP 3 R blockade triggered the autophagy of both ER and mitochondria, as exactly observed in starvation-induced autophagy. ER stressors such as tunicamycin and thapsigargin also induced autophagy of ER and, to less extent, of mitochondria. Autophagy triggered by starvation or IP 3 R blockade was inhibited by Bcl-2 and Bcl-X L specifically targeted to ER but not Bcl-2 or Bcl-X L proteins targeted to mitochondria. In contrast, ER stress-induced autophagy was not inhibited by Bcl-2 and Bcl-X L. Autophagy promoted by IP 3 R inhibition could not be attributed to a modulation of steady-state Ca 2+ levels in the ER or in the cytosol, yet involved the obligate contribution of Beclin-1, autophagy-related gene (Atg) 5, Atg10, Atg12 and hVps34. Altogether, these results strongly suggest that IP 3 R exerts a major role in the physiological control of autophagy.