The pathways that allow quiescent disseminated cancer cells to survive during prolonged dormancy periods are unknown. Here, we identify the transcription factor ATF6α as a pivotal survival factor for quiescent but not proliferative squamous carcinoma cells. ATF6α is essential for the adaptation of dormant cells to chemotherapy, nutritional stress, and, most importantly, the in vivo microenvironment. Mechanism analysis showed that MKK6 and p38α/β contribute to regulating nuclear translocation and transcriptional activation of ATF6α in dormant cancer cells. Downstream, ATF6α induces survival through the up-regulation of Rheb and activation of mTOR signaling independent of Akt. Down-regulation of ATF6α or Rheb reverted dormant tumor cell resistance to rapamycin and induced pronounced killing only of dormant cancer cells in vivo . Knocking down ATF6α also prolonged the survival of nude mice bearing dormant tumor cells. Targeting survival signaling by the ATF6α-Rheb-mTOR pathway in dormant tumor cells may favor the eradication of residual disease during dormancy periods.