Macroautophagy has been implicated as a mechanism of cell death. However, the relationship between this degradative pathway and cell death is unclear as macroautophagy has been shown recently to protect against apoptosis. To better define the interplay between these two critical cellular processes, we determined whether inhibition of macroautophagy could have both pro- and anti-apoptotic effects in the same cell. Mouse embryonic fibroblasts (MEFs) from mice with a knockout of the essential macroautophagy gene ATG5 were treated with activators of the extrinsic and intrinsic death pathways. Loss of macroautophagy sensitized these cells to caspase-dependent apoptosis from the death receptor ligands Fas and tumor necrosis factor- (TNF). Atg5^-/- MEFs had increased activation of the mitochondrial death pathway in response to Fas/TNF in concert with decreased ATP levels. Fas/TNF treatment failed to up regulate macroautophagy and in fact decreased activity at late time points. In contrast to their sensitization to Fas/TNF, Atg5^-/- cells were resistant to death from menadione and UV light. In the absence of macroautophagy, an up regulation of chaperone-mediated autophagy (CMA) induced resistance to these stressors. These results demonstrate that inhibition of macroautophagy can promote or prevent apoptosis in the same cell, and that the response is governed by the nature of the death stimulus and compensatory changes in other forms of autophagy. Experimental findings that an inhibition of macroautophagy blocks apoptosis does not prove that autophagy mediates cell death as this effect may result from the protective up regulation of other autophagic pathways such as CMA.